@article {963, title = {Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency.}, journal = {Blood}, volume = {137}, year = {2021}, month = {2021 01 28}, pages = {493-499}, abstract = {

Agammaglobulinemia is the most profound primary antibody deficiency that can occur due to an early termination of B-cell development. We here investigated 3 novel patients, including the first known adult, from unrelated families with agammaglobulinemia, recurrent infections, and hypertrophic cardiomyopathy (HCM). Two of them also presented with intermittent or severe chronic neutropenia. We identified homozygous or compound-heterozygous variants in the gene for folliculin interacting protein 1 (FNIP1), leading to loss of the FNIP1 protein. B-cell metabolism, including mitochondrial numbers and activity and phosphatidylinositol 3-kinase/AKT pathway, was impaired. These defects recapitulated the Fnip1-/- animal model. Moreover, we identified either uniparental disomy or copy-number variants (CNVs) in 2 patients, expanding the variant spectrum of this novel inborn error of immunity. The results indicate that FNIP1 deficiency can be caused by complex genetic mechanisms and support the clinical utility of exome sequencing and CNV analysis in patients with broad phenotypes, including agammaglobulinemia and HCM. FNIP1 deficiency is a novel inborn error of immunity characterized by early and severe B-cell development defect, agammaglobulinemia, variable neutropenia, and HCM. Our findings elucidate a functional and relevant role of FNIP1 in B-cell development and metabolism and potentially neutrophil activity.

}, keywords = {Adult, Agammaglobulinemia, Animals, B-Lymphocytes, Cardiomyopathy, Hypertrophic, Carrier Proteins, Child, Child, Preschool, Chromosomes, Human, Pair 5, Codon, Nonsense, Consanguinity, Crohn Disease, Developmental Disabilities, Disease Models, Animal, Disease Susceptibility, DNA Copy Number Variations, Female, Heart Defects, Congenital, Humans, Immunologic Deficiency Syndromes, Infections, Loss of Function Mutation, Lymphopenia, Male, Mice, Neutropenia, Pedigree, Uniparental Disomy, Whole Exome Sequencing}, issn = {1528-0020}, doi = {10.1182/blood.2020006441}, author = {Saettini, Francesco and Poli, Cecilia and Vengoechea, Jaime and Bonanomi, Sonia and Orellana, Julio C and Fazio, Grazia and Rodriguez, Fred H and Noguera, Loreani P and Booth, Claire and Jarur-Chamy, Valentina and Shams, Marissa and Iascone, Maria and Vukic, Maja and Gasperini, Serena and Quadri, Manuel and Barroeta Seijas, Amairelys and Rivers, Elizabeth and Mauri, Mario and Badolato, Raffaele and Cazzaniga, Gianni and Bugarin, Cristina and Gaipa, Giuseppe and Kroes, Wilma G M and Moratto, Daniele and van Oostaijen-Ten Dam, Monique M and Baas, Frank and van der Maarel, Silv{\`e}re and Piazza, Rocco and Coban-Akdemir, Zeynep H and Lupski, James R and Yuan, Bo and Chinn, Ivan K and Daxinger, Lucia and Biondi, Andrea} } @article {916, title = {Biallelic variants in HPDL, encoding 4-hydroxyphenylpyruvate dioxygenase-like protein, lead to an infantile neurodegenerative condition.}, journal = {Genet Med}, volume = {23}, year = {2021}, month = {2021 03}, pages = {524-533}, abstract = {

PURPOSE: Dioxygenases are oxidoreductase enzymes with roles in metabolic pathways necessary for aerobic life. 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL), encoded by HPDL, is an orphan paralogue of 4-hydroxyphenylpyruvate dioxygenase (HPD), an iron-dependent dioxygenase involved in tyrosine catabolism. The function and association of HPDL with human diseases remain unknown.

METHODS: We applied exome sequencing in a cohort of over 10,000 individuals with neurodevelopmental diseases. Effects of HPDL loss were investigated in vitro and in vivo, and through mass spectrometry analysis. Evolutionary analysis was performed to investigate the potential functional separation of HPDL from HPD.

RESULTS: We identified biallelic variants in HPDL in eight families displaying recessive inheritance. Knockout mice closely phenocopied humans and showed evidence of apoptosis in multiple cellular lineages within the cerebral cortex. HPDL is a single-exonic gene that likely arose from a retrotransposition event at the base of the tetrapod lineage, and unlike HPD, HPDL is mitochondria-localized. Metabolic profiling of HPDL mutant cells and mice showed no evidence of altered tyrosine metabolites, but rather notable accumulations in other metabolic pathways.

CONCLUSION: The mitochondrial localization, along with its disrupted metabolic profile, suggests HPDL loss in humans links to a unique neurometabolic mitochondrial infantile neurodegenerative condition.

}, keywords = {4-Hydroxyphenylpyruvate Dioxygenase, Animals, Dioxygenases, Exons, Mice, Mice, Knockout, Phenotype}, issn = {1530-0366}, doi = {10.1038/s41436-020-01010-y}, author = {Ghosh, Shereen G and Lee, Sangmoon and Fabunan, Rudy and Chai, Guoliang and Zaki, MAH S and Abdel-Salam, Ghada and Sultan, Tipu and Ben-Omran, Tawfeg and Alvi, Javeria Raza and McEvoy-Venneri, Jennifer and Stanley, Valentina and Patel, Aakash and Ross, Danica and Ding, Jeffrey and Jain, Mohit and Pan, Daqiang and L{\"u}bbert, Philipp and Kammerer, Bernd and Wiedemann, Nils and Verhoeven-Duif, Nanda M and Jans, Judith J and Murphy, David and Toosi, Mehran Beiraghi and Ashrafzadeh, Farah and Imannezhad, Shima and Karimiani, Ehsan Ghayoor and Ibrahim, Khalid and Waters, Elizabeth R and Maroofian, Reza and Gleeson, Joseph G} } @article {1007, title = {De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis.}, journal = {Am J Hum Genet}, volume = {108}, year = {2021}, month = {2021 02 04}, pages = {357-367}, abstract = {

Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p = 3.28~{\texttimes} 10). In all six cases with available parental DNA, we demonstrated de novo inheritance (p~=~2.21~{\texttimes} 10). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease.

}, keywords = {Adult, Animals, Carrier Proteins, Cell Line, Child, Child, Preschool, Codon, Nonsense, Developmental Disabilities, Epilepsy, Female, Glomerulosclerosis, Focal Segmental, Humans, Intranuclear Space, Kidney, Male, Mice, Mutation, Nephrotic Syndrome, Nerve Tissue Proteins, Phenotype, Podocytes, Whole Exome Sequencing}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.01.008}, author = {Weng, Patricia L and Majmundar, Amar J and Khan, Kamal and Lim, Tze Y and Shril, Shirlee and Jin, Gina and Musgrove, John and Wang, Minxian and Ahram, Dina F and Aggarwal, Vimla S and Bier, Louise E and Heinzen, Erin L and Onuchic-Whitford, Ana C and Mann, Nina and Buerger, Florian and Schneider, Ronen and Deutsch, Konstantin and Kitzler, Thomas M and Kl{\"a}mbt, Verena and Kolb, Amy and Mao, Youying and Moufawad El Achkar, Christelle and Mitrotti, Adele and Martino, Jeremiah and Beck, Bodo B and Altm{\"u}ller, Janine and Benz, Marcus R and Yano, Shoji and Mikati, Mohamad A and Gunduz, Talha and Cope, Heidi and Shashi, Vandana and Trachtman, Howard and Bodria, Monica and Caridi, Gianluca and Pisani, Isabella and Fiaccadori, Enrico and AbuMaziad, Asmaa S and Martinez-Agosto, Julian A and Yadin, Ora and Zuckerman, Jonathan and Kim, Arang and John-Kroegel, Ulrike and Tyndall, Amanda V and Parboosingh, Jillian S and Innes, A Micheil and Bierzynska, Agnieszka and Koziell, Ania B and Muorah, Mordi and Saleem, Moin A and Hoefele, Julia and Riedhammer, Korbinian M and Gharavi, Ali G and Jobanputra, Vaidehi and Pierce-Hoffman, Emma and Seaby, Eleanor G and O{\textquoteright}Donnell-Luria, Anne and Rehm, Heidi L and Mane, Shrikant and D{\textquoteright}Agati, Vivette D and Pollak, Martin R and Ghiggeri, Gian Marco and Lifton, Richard P and Goldstein, David B and Davis, Erica E and Hildebrandt, Friedhelm and Sanna-Cherchi, Simone} } @article {1021, title = {Deletion of CTCF sites in the SHH locus alters enhancer-promoter interactions and leads to acheiropodia.}, journal = {Nat Commun}, volume = {12}, year = {2021}, month = {2021 04 16}, pages = {2282}, abstract = {

Acheiropodia, congenital limb truncation, is associated with homozygous deletions in the LMBR1 gene around ZRS, an enhancer regulating SHH during limb development. How these deletions lead to this phenotype is unknown. Using whole-genome sequencing, we fine-mapped the acheiropodia-associated region to 12 kb and show that it does not function as an enhancer. CTCF and RAD21 ChIP-seq together with 4C-seq and DNA FISH identify three CTCF sites within the acheiropodia-deleted region that mediate the interaction between the ZRS and the SHH promoter. This interaction is substituted with other CTCF sites centromeric to the ZRS in the disease state. Mouse knockouts of the orthologous 12 kb sequence have no apparent abnormalities, showcasing the challenges in modelling CTCF alterations in animal models due to inherent motif differences between species. Our results show that alterations in CTCF motifs can lead to a Mendelian condition due to altered enhancer-promoter interactions.

}, keywords = {Animals, Binding Sites, CCCTC-Binding Factor, Chromatin Immunoprecipitation Sequencing, Disease Models, Animal, Embryo, Mammalian, Enhancer Elements, Genetic, Exons, Extremities, Female, Foot Deformities, Congenital, Gene Expression Regulation, Developmental, Genetic Loci, Genetic Testing, Hand Deformities, Congenital, Hedgehog Proteins, Humans, Introns, Male, Membrane Proteins, Mice, Mice, Knockout, Promoter Regions, Genetic, Sequence Deletion, Species Specificity, Whole Genome Sequencing}, issn = {2041-1723}, doi = {10.1038/s41467-021-22470-z}, author = {Ushiki, Aki and Zhang, Yichi and Xiong, Chenling and Zhao, Jingjing and Georgakopoulos-Soares, Ilias and Kane, Lauren and Jamieson, Kirsty and Bamshad, Michael J and Nickerson, Deborah A and Shen, Yin and Lettice, Laura A and Silveira-Lucas, Elizabeth Lemos and Petit, Florence and Ahituv, Nadav} } @article {1003, title = {Inhibition of HECT E3 ligases as potential therapy for COVID-19.}, journal = {Cell Death Dis}, volume = {12}, year = {2021}, month = {2021 03 24}, pages = {310}, abstract = {

SARS-CoV-2 is responsible for the ongoing world-wide pandemic which has already taken more than two million lives. Effective treatments are urgently needed. The enzymatic activity of the HECT-E3 ligase family members has been implicated in the cell egression phase of deadly RNA viruses such as Ebola through direct interaction of its VP40 Protein. Here we report that HECT-E3 ligase family members such as NEDD4 and WWP1 interact with and ubiquitylate the SARS-CoV-2 Spike protein. Furthermore, we find that HECT family members are overexpressed in primary samples derived from COVID-19 infected patients and COVID-19 mouse models. Importantly, rare germline activating variants in the NEDD4 and WWP1 genes are associated with severe COVID-19 cases. Critically, I3C, a natural NEDD4 and WWP1 inhibitor from Brassicaceae, displays potent antiviral effects and inhibits viral egression. In conclusion, we identify the HECT family members of E3 ligases as likely novel biomarkers for COVID-19, as well as new potential targets of therapeutic strategy easily testable in clinical trials in view of the established well-tolerated nature of the Brassicaceae natural compounds.

}, keywords = {Adult, Aged, Animals, Antiviral Agents, Chlorocebus aethiops, COVID-19, Endosomal Sorting Complexes Required for Transport, Female, Humans, Indoles, Male, Mice, Mice, Inbred BALB C, Middle Aged, Nedd4 Ubiquitin Protein Ligases, SARS-CoV-2, Spike Glycoprotein, Coronavirus, Ubiquitin-Protein Ligases, Ubiquitination, Vero Cells}, issn = {2041-4889}, doi = {10.1038/s41419-021-03513-1}, author = {Novelli, Giuseppe and Liu, Jing and Biancolella, Michela and Alonzi, Tonino and Novelli, Antonio and Patten, J J and Cocciadiferro, Dario and Agolini, Emanuele and Colona, Vito Luigi and Rizzacasa, Barbara and Giannini, Rosalinda and Bigio, Benedetta and Goletti, Delia and Capobianchi, Maria Rosaria and Grelli, Sandro and Mann, Justin and McKee, Trevor D and Cheng, Ke and Amanat, Fatima and Krammer, Florian and Guarracino, Andrea and Pepe, Gerardo and Tomino, Carlo and Tandjaoui-Lambiotte, Yacine and Uzunhan, Yurdagul and Tubiana, Sarah and Ghosn, Jade and Notarangelo, Luigi D and Su, Helen C and Abel, Laurent and Cobat, Aurelie and Elhanan, Gai and Grzymski, Joseph J and Latini, Andrea and Sidhu, Sachdev S and Jain, Suresh and Davey, Robert A and Casanova, Jean-Laurent and Wei, Wenyi and Pandolfi, Pier Paolo} } @article {924, title = {Mutations in Spliceosomal Genes PPIL1 and PRP17 Cause Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly.}, journal = {Neuron}, volume = {109}, year = {2021}, month = {2021 01 20}, pages = {241-256.e9}, abstract = {

Autosomal-recessive cerebellar hypoplasia and ataxia constitute a group of heterogeneous brain disorders caused by disruption of several fundamental cellular processes. Here, we identified 10 families showing a neurodegenerative condition involving pontocerebellar hypoplasia with microcephaly (PCHM). Patients harbored biallelic mutations in genes encoding the spliceosome components Peptidyl-Prolyl Isomerase Like-1 (PPIL1) or Pre-RNA Processing-17 (PRP17). Mouse knockouts of either gene were lethal in early embryogenesis, whereas PPIL1 patient mutation knockin mice showed neuron-specific apoptosis. Loss of either protein affected splicing integrity, predominantly affecting short and high GC-content introns and genes involved in brain disorders. PPIL1 and PRP17 form an active isomerase-substrate interaction, but we found that isomerase activity is not critical for function. Thus, we establish disrupted splicing integrity and "major spliceosome-opathies" as a new mechanism underlying PCHM and neurodegeneration and uncover a non-enzymatic function of a spliceosomal proline isomerase.

}, keywords = {Amino Acid Sequence, Animals, Cell Cycle Proteins, Cerebellar Diseases, Cohort Studies, Female, Gene Knockout Techniques, HEK293 Cells, Heredodegenerative Disorders, Nervous System, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microcephaly, Mutation, Pedigree, Peptidylprolyl Isomerase, Protein Structure, Secondary, Protein Structure, Tertiary, RNA Splicing Factors, Spliceosomes}, issn = {1097-4199}, doi = {10.1016/j.neuron.2020.10.035}, author = {Chai, Guoliang and Webb, Alice and Li, Chen and Antaki, Danny and Lee, Sangmoon and Breuss, Martin W and Lang, Nhi and Stanley, Valentina and Anzenberg, Paula and Yang, Xiaoxu and Marshall, Trevor and Gaffney, Patrick and Wierenga, Klaas J and Chung, Brian Hon-Yin and Tsang, Mandy Ho-Yin and Pais, Lynn S and Lovgren, Alysia Kern and VanNoy, Grace E and Rehm, Heidi L and Mirzaa, Ghayda and Leon, Eyby and Diaz, Jullianne and Neumann, Alexander and Kalverda, Arnout P and Manfield, Iain W and Parry, David A and Logan, Clare V and Johnson, Colin A and Bonthron, David T and Valleley, Elizabeth M A and Issa, Mahmoud Y and Abdel-Ghafar, Sherif F and Abdel-Hamid, Mohamed S and Jennings, Patricia and Zaki, MAH S and Sheridan, Eamonn and Gleeson, Joseph G} } @article {991, title = {Mutations in transcription factor CP2-like 1 may cause a novel syndrome with distal renal tubulopathy in humans.}, journal = {Nephrol Dial Transplant}, volume = {36}, year = {2021}, month = {2021 01 25}, pages = {237-246}, abstract = {

BACKGROUND: An underlying monogenic cause of early-onset chronic kidney disease (CKD) can be detected in \~{}20\% of individuals. For many etiologies of CKD manifesting before 25 years of age, >200 monogenic causative genes have been identified to date, leading to the elucidation of mechanisms of renal pathogenesis.

METHODS: In 51 families with echogenic kidneys and CKD, we performed whole-exome sequencing to identify novel monogenic causes of CKD.

RESULTS: We discovered a homozygous truncating mutation in the transcription factor gene transcription factor CP2-like 1 (TFCP2L1) in an Arabic patient of consanguineous descent. The patient developed CKD by the age of 2 months and had episodes of severe hypochloremic, hyponatremic and hypokalemic alkalosis, seizures, developmental delay and hypotonia together with cataracts. We found that TFCP2L1~was localized throughout kidney development particularly in the distal nephron. Interestingly, TFCP2L1 induced the growth and development of renal tubules from rat mesenchymal cells. Conversely, the deletion of TFCP2L1~in mice was previously shown to lead to reduced expression of renal cell markers including ion transporters and cell identity proteins expressed in different segments of the distal nephron. TFCP2L1 localized to the nucleus in HEK293T cells only upon coexpression with its paralog upstream-binding protein 1 (UBP1). A TFCP2L1 mutant complementary DNA (cDNA) clone that represented the patient{\textquoteright}s mutation failed to form homo- and heterodimers with UBP1, an essential step for its transcriptional activity.

CONCLUSION: Here, we identified a loss-of-function TFCP2L1 mutation as a potential novel cause of CKD in childhood accompanied by a salt-losing tubulopathy.

}, keywords = {Animals, Child, DNA-Binding Proteins, Epithelial-Mesenchymal Transition, Female, HEK293 Cells, Humans, Kidney Diseases, Mice, Mice, Knockout, Mutation, Rats, Repressor Proteins, Single-Cell Analysis, Transcription Factors, Whole Exome Sequencing}, issn = {1460-2385}, doi = {10.1093/ndt/gfaa215}, author = {Kl{\"a}mbt, Verena and Werth, Max and Onuchic-Whitford, Ana C and Getwan, Maike and Kitzler, Thomas M and Buerger, Florian and Mao, Youying and Deutsch, Konstantin and Mann, Nina and Majmundar, Amar J and Kaminski, Michael M and Shen, Tian and Schmidt-Ott, Kai M and Shalaby, Mohamed and El Desoky, Sherif and Kari, Jameela A and Shril, Shirlee and Lienkamp, Soeren S and Barasch, Jonathan and Hildebrandt, Friedhelm} } @article {976, title = {Beyond the tubule: pathological variants of , encoding the megalin receptor, result in glomerular loss and early progressive chronic kidney disease.}, journal = {Am J Physiol Renal Physiol}, volume = {319}, year = {2020}, month = {2020 12 01}, pages = {F988-F999}, abstract = {

Pathogenic variants in the gene, encoding the multiligand receptor megalin, cause a rare autosomal recessive syndrome: Donnai-Barrow/Facio-Oculo-Acoustico-Renal (DB/FOAR) syndrome. Because of the rarity of the syndrome, the long-term consequences of the tubulopathy on human renal health have been difficult to ascertain, and the human clinical condition has hitherto been characterized as a benign tubular condition with asymptomatic low-molecular-weight proteinuria. We investigated renal function and morphology in a murine model of DB/FOAR syndrome and in patients with DB/FOAR. We analyzed glomerular filtration rate in mice by FITC-inulin clearance and clinically characterized six families, including nine patients with DB/FOAR and nine family members. Urine samples from patients were analyzed by Western blot analysis and biopsy materials were analyzed by histology. In the mouse model, we used histological methods to assess nephrogenesis and postnatal renal structure and contrast-enhanced magnetic resonance imaging to assess glomerular number. In megalin-deficient mice, we found a lower glomerular filtration rate and an increase in the abundance of injury markers, such as kidney injury molecule-1 and -acetyl-β-d-glucosaminidase. Renal injury was validated in patients, who presented with increased urinary kidney injury molecule-1, classical markers of chronic kidney disease, and glomerular proteinuria early in life. Megalin-deficient mice had normal nephrogenesis, but they had 19\% fewer nephrons in early adulthood and an increased fraction of nephrons with disconnected glomerulotubular junction. In conclusion, megalin dysfunction, as present in DB/FOAR syndrome, confers an increased risk of progression into chronic kidney disease.

}, keywords = {Adolescent, Adult, Animals, Child, Child, Preschool, Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Kidney Glomerulus, Low Density Lipoprotein Receptor-Related Protein-2, Male, Mice, Mice, Knockout, Middle Aged, Renal Insufficiency, Chronic, Young Adult}, issn = {1522-1466}, doi = {10.1152/ajprenal.00295.2020}, author = {Charlton, Jennifer R and Tan, Weizhen and Daouk, Ghaleb and Teot, Lisa and Rosen, Seymour and Bennett, Kevin M and Cwiek, Aleksandra and Nam, Sejin and Emma, Francesco and Jouret, Fran{\c c}ois and Oliveira, Jo{\~a}o Paulo and Tranebj{\ae}rg, Lisbeth and Frykholm, Carina and Mane, Shrikant and Hildebrandt, Friedhelm and Srivastava, Tarak and Storm, Tina and Christensen, Erik Ils{\o} and Nielsen, Rikke} } @article {777, title = {Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide.}, journal = {Eur J Hum Genet}, volume = {28}, year = {2020}, month = {2020 09}, pages = {1243-1264}, abstract = {

Previously we reported the identification of a homozygous COL27A1 (c.2089G>C; p.Gly697Arg) missense variant and proposed it as a founder allele in Puerto Rico segregating with Steel syndrome (STLS, MIM $\#$615155); a rare osteochondrodysplasia characterized by short stature, congenital bilateral hip dysplasia, carpal coalitions, and scoliosis. We now report segregation of this variant in five probands from the initial clinical report defining the syndrome and an additional family of Puerto Rican descent with multiple affected adult individuals. We modeled the orthologous variant in murine Col27a1 and found it recapitulates some of the major Steel syndrome associated skeletal features including reduced body length, scoliosis, and a more rounded skull shape. Characterization of the in vivo murine model shows abnormal collagen deposition in the extracellular matrix and disorganization of the proliferative zone of the growth plate. We report additional COL27A1 pathogenic variant alleles identified in unrelated consanguineous Turkish kindreds suggesting Clan Genomics and identity-by-descent homozygosity contributing to disease in this population. The hypothesis that carrier states for this autosomal recessive osteochondrodysplasia may contribute to common complex traits is further explored in a large clinical population cohort. Our findings augment our understanding of COL27A1 biology and its role in skeletal development; and expand the functional allelic architecture in this gene underlying both rare and common disease phenotypes.

}, keywords = {Abnormalities, Multiple, Adolescent, Animals, Bone Development, Child, Child, Preschool, Consanguinity, Extracellular Matrix, Female, Fibrillar Collagens, Founder Effect, Gene Frequency, Hip Dislocation, Homozygote, Humans, Male, Mice, Mice, Inbred C57BL, Mutation, Pedigree, Scoliosis, Syndrome}, issn = {1476-5438}, doi = {10.1038/s41431-020-0632-x}, author = {Gonzaga-Jauregui, Claudia and Yesil, G{\"o}zde and Nistala, Harikiran and Gezdirici, Alper and Bayram, Yavuz and Nannuru, Kalyan C and Pehlivan, Davut and Yuan, Bo and Jimenez, Johanna and Sahin, Yavuz and Paine, Ingrid S and Akdemir, Zeynep Coban and Rajamani, Saathyaki and Staples, Jeffrey and Dronzek, John and Howell, Kristen and Fatih, Jawid M and Smaldone, Silvia and Schlesinger, Alan E and Ram{\'\i}rez, Norman and Cornier, Alberto S and Kelly, Melissa A and Haber, Robert and Chim, Shek Man and Nieman, Kristy and Wu, Nan and Walls, Johnathon and Poueymirou, William and Siao, Chia-Jen and Sutton, V Reid and Williams, Marc S and Posey, Jennifer E and Gibbs, Richard A and Carlo, Simon and Tegay, David H and Economides, Aris N and Lupski, James R} } @article {828, title = {Loss of the neural-specific BAF subunit ACTL6B relieves repression of early response genes and causes recessive autism.}, journal = {Proc Natl Acad Sci U S A}, volume = {117}, year = {2020}, month = {2020 05 05}, pages = {10055-10066}, abstract = {

Synaptic activity in neurons leads to the rapid activation of genes involved in mammalian behavior. ATP-dependent chromatin remodelers such as the BAF complex contribute to these responses and are generally thought to activate transcription. However, the mechanisms keeping such "early activation" genes silent have been a mystery. In the course of investigating Mendelian recessive autism, we identified six families with segregating loss-of-function mutations in the neuronal BAF (nBAF) subunit (originally named ). Accordingly, was the most significantly mutated gene in the Simons Recessive Autism Cohort. At least 14 subunits of the nBAF complex are mutated in autism, collectively making it a major contributor to autism spectrum disorder (ASD). Patient mutations destabilized ACTL6B protein in neurons and rerouted dendrites to the wrong glomerulus in the fly olfactory system. Humans and mice lacking showed corpus callosum hypoplasia, indicating a conserved role for in facilitating neural connectivity. knockout mice on two genetic backgrounds exhibited ASD-related behaviors, including social and memory impairments, repetitive behaviors, and hyperactivity. Surprisingly, mutation of relieved repression of early response genes including AP1 transcription factors (, , , and ), increased chromatin accessibility at AP1 binding sites, and transcriptional changes in late response genes associated with early response transcription factor activity. loss is thus an important cause of recessive ASD, with impaired neuron-specific chromatin repression indicated as a potential mechanism.

}, keywords = {Actins, Adenosine Triphosphate, Animals, Autism Spectrum Disorder, Behavior, Animal, Chromatin, Chromatin Assembly and Disassembly, Chromosomal Proteins, Non-Histone, Chromosome Pairing, Corpus Callosum, Dendrites, Disease Models, Animal, DNA-Binding Proteins, Gene Expression Regulation, Hippocampus, Humans, Mice, Mice, Knockout, Mutation, Neurons, Transcription Factors}, issn = {1091-6490}, doi = {10.1073/pnas.1908238117}, author = {Wenderski, Wendy and Wang, Lu and Krokhotin, Andrey and Walsh, Jessica J and Li, Hongjie and Shoji, Hirotaka and Ghosh, Shereen and George, Renee D and Miller, Erik L and Elias, Laura and Gillespie, Mark A and Son, Esther Y and Staahl, Brett T and Baek, Seung Tae and Stanley, Valentina and Moncada, Cynthia and Shipony, Zohar and Linker, Sara B and Marchetto, Maria C N and Gage, Fred H and Chen, Dillon and Sultan, Tipu and Zaki, MAH S and Ranish, Jeffrey A and Miyakawa, Tsuyoshi and Luo, Liqun and Malenka, Robert C and Crabtree, Gerald R and Gleeson, Joseph G} } @article {749, title = {A missense mutation in the catalytic domain of O-GlcNAc transferase links perturbations in protein O-GlcNAcylation to X-linked intellectual disability.}, journal = {FEBS Lett}, volume = {594}, year = {2020}, month = {2020 02}, pages = {717-727}, abstract = {

X-linked intellectual disabilities (XLID) are common developmental disorders. The enzyme O-GlcNAc transferase encoded by OGT, a recently discovered XLID gene, attaches O-GlcNAc to nuclear and cytoplasmic proteins. As few missense mutations have been described, it is unclear what the aetiology of the patient phenotypes is. Here, we report the discovery of a missense mutation in the catalytic domain of OGT in an XLID patient. X-ray crystallography reveals that this variant leads to structural rearrangements in the catalytic domain. The mutation reduces in~vitro OGT activity on substrate peptides/protein. Mouse embryonic stem cells carrying the mutation reveal reduced O-GlcNAcase (OGA) and global O-GlcNAc levels. These data suggest a direct link between changes in the O-GlcNAcome and intellectual disability observed in patients carrying OGT mutations.

}, keywords = {Animals, Catalytic Domain, Cell Line, Glycosylation, Humans, Intellectual Disability, Mice, Models, Molecular, Mutation, Missense, N-Acetylglucosaminyltransferases}, issn = {1873-3468}, doi = {10.1002/1873-3468.13640}, author = {Pravata, Veronica M and Gundogdu, Mehmet and Bartual, Sergio G and Ferenbach, Andrew T and Stavridis, Marios and {\~O}unap, Katrin and Pajusalu, Sander and {\v Z}ordania, Riina and Wojcik, Monica H and van Aalten, Daan M F} } @article {800, title = {Multi-omic studies on missense PLG variants in families with otitis media.}, journal = {Sci Rep}, volume = {10}, year = {2020}, month = {2020 09 14}, pages = {15035}, abstract = {

Otitis media (OM), a very common disease in young children, can result in hearing loss. In order to potentially replicate previously reported associations between OM and PLG, exome and Sanger sequencing, RNA-sequencing of saliva and middle ear samples, 16S rRNA sequencing, molecular modeling, and statistical analyses including transmission disequilibrium tests (TDT) were performed in a multi-ethnic cohort of 718 families and simplex cases with OM. We identified four rare PLG variants c.112A > G (p.Lys38Glu), c.782G > A (p.Arg261His), c.1481C > T (p.Ala494Val) and c.2045~T > A (p.Ile682Asn), and one common variant c.1414G > A (p.Asp472Asn). However TDT analyses for these PLG variants did not demonstrate association with OM in 314 families. Additionally PLG expression is very low or absent in normal or diseased middle ear in mouse and human, and salivary expression and microbial α-diversity were non-significant in c.1414G > A (p.Asp472Asn) carriers. Based on molecular modeling, the novel rare variants particularly c.782G > A (p.Arg261His) and c.2045~T > A (p.Ile682Asn) were predicted to affect protein structure. Exploration of other potential disease mechanisms will help elucidate how PLG contributes to OM susceptibility in humans. Our results underline the importance of following up findings from genome-wide association through replication studies, preferably using multi-omic datasets.

}, keywords = {Animals, Ear, Middle, Female, Genomics, Humans, Male, Mice, Microbiota, Mutation, Missense, Otitis Media, Pedigree, Plasminogen, Polymorphism, Single Nucleotide, Saliva}, issn = {2045-2322}, doi = {10.1038/s41598-020-70498-w}, author = {Bootpetch, Tori C and Hafr{\'e}n, Lena and Elling, Christina L and Baschal, Erin E and Manichaikul, Ani W and Pine, Harold S and Szeremeta, Wasyl and Scholes, Melissa A and Cass, Stephen P and Larson, Eric D and Chan, Kenny H and Ishaq, Rafaqat and Prager, Jeremy D and Shaikh, Rehan S and Gubbels, Samuel P and Yousaf, Ayesha and Wine, Todd M and Bamshad, Michael J and Yoon, Patricia J and Jenkins, Herman A and Nickerson, Deborah A and Streubel, Sven-Olrik and Friedman, Norman R and Frank, Daniel N and Einarsdottir, Elisabet and Kere, Juha and Riazuddin, Saima and Daly, Kathleen A and Leal, Suzanne M and Ryan, Allen F and Mattila, Petri S and Ahmed, Zubair M and Sale, Michele M and Chonmaitree, Tasnee and Santos-Cortez, Regie Lyn P} } @article {970, title = {A mutation affecting laminin alpha 5 polymerisation gives rise to a syndromic developmental disorder.}, journal = {Development}, volume = {147}, year = {2020}, month = {2020 06 22}, abstract = {

Laminin alpha 5 (LAMA5) is a member of a large family of proteins that trimerise and then polymerise to form a central component of all basement membranes. Consequently, the protein plays an instrumental role in shaping the normal development of the kidney, skin, neural tube, lung and limb, and many other organs and tissues. Pathogenic mutations in some laminins have been shown to cause a range of largely syndromic conditions affecting the competency of the basement membranes to which they contribute. We report the identification of a mutation in the polymerisation domain of LAMA5 in a patient with a complex syndromic disease characterised by defects in kidney, craniofacial and limb development, and by a range of other congenital defects. Using CRISPR-generated mouse models and biochemical assays, we demonstrate the pathogenicity of this variant, showing that the change results in a failure of the polymerisation of α/β/γ laminin trimers. Comparing these phenotypes with those apparent upon gene deletion in mice provides insights into the specific functional importance of laminin polymerisation during development and tissue homeostasis.

}, keywords = {Amino Acid Sequence, Animals, Animals, Newborn, Child, Preschool, Developmental Disabilities, Fetal Development, Fetus, Humans, Hydronephrosis, Infant, Newborn, Kidney, Laminin, Lung, Male, Mice, Mutation, Polymerization, Protein Domains, Syndrome}, issn = {1477-9129}, doi = {10.1242/dev.189183}, author = {Jones, Lynelle K and Lam, Rachel and McKee, Karen K and Aleksandrova, Maya and Dowling, John and Alexander, Stephen I and Mallawaarachchi, Amali and Cottle, Denny L and Short, Kieran M and Pais, Lynn and Miner, Jeffery H and Mallett, Andrew J and Simons, Cas and McCarthy, Hugh and Yurchenco, Peter D and Smyth, Ian M} } @article {807, title = {Mutation of CFAP57, a protein required for the asymmetric targeting of a subset of inner dynein arms in Chlamydomonas, causes primary ciliary dyskinesia.}, journal = {PLoS Genet}, volume = {16}, year = {2020}, month = {2020 08}, pages = {e1008691}, abstract = {

Primary ciliary dyskinesia (PCD) is characterized by chronic airway disease, reduced fertility, and randomization of the left/right body axis. It is caused by defects of motile cilia and sperm flagella. We screened a cohort of affected individuals that lack an obvious axonemal defect for pathogenic variants using whole exome capture, next generation sequencing, and bioinformatic analysis assuming an autosomal recessive trait. We identified one subject with an apparently homozygous nonsense variant [(c.1762C>T), p.(Arg588*)] in the uncharacterized CFAP57 gene. Interestingly, the variant results in the skipping of exon 11 (58 amino acids), which may be due to disruption of an exonic splicing enhancer. In normal human nasal epithelial cells, CFAP57 localizes throughout the ciliary axoneme. Nasal cells from the PCD patient express a shorter, mutant version of CFAP57 and the protein is not incorporated into the axoneme. The missing 58 amino acids include portions of WD repeats that may be important for loading onto the intraflagellar transport (IFT) complexes for transport or docking onto the axoneme. A reduced beat frequency and an alteration in ciliary waveform was observed. Knockdown of CFAP57 in human tracheobronchial epithelial cells (hTECs) recapitulates these findings. Phylogenetic analysis showed that CFAP57 is highly conserved in organisms that assemble motile cilia. CFAP57 is allelic with the BOP2/IDA8/FAP57 gene identified previously in Chlamydomonas reinhardtii. Two independent, insertional fap57 Chlamydomonas mutant strains show reduced swimming velocity and altered waveforms. Tandem mass tag (TMT) mass spectroscopy shows that FAP57 is missing, and the "g" inner dyneins (DHC7 and DHC3) and the "d" inner dynein (DHC2) are reduced, but the FAP57 paralog FBB7 is increased. Together, our data identify a homozygous variant in CFAP57 that causes PCD that is likely due to a defect in the inner dynein arm assembly process.

}, keywords = {3T3 Cells, Adult, Animals, Axoneme, Cells, Cultured, Chlamydomonas reinhardtii, Cilia, Ciliary Motility Disorders, Codon, Nonsense, Conserved Sequence, Dyneins, Humans, Male, Mice, Microtubule-Associated Proteins, Plant Proteins, Proteins, Respiratory Mucosa}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1008691}, author = {Bustamante-Marin, Ximena M and Horani, Amjad and Stoyanova, Mihaela and Charng, Wu-Lin and Bottier, Mathieu and Sears, Patrick R and Yin, Wei-Ning and Daniels, Leigh Anne and Bowen, Hailey and Conrad, Donald F and Knowles, Michael R and Ostrowski, Lawrence E and Zariwala, Maimoona A and Dutcher, Susan K} } @article {907, title = {Mutations of the Transcriptional Corepressor ZMYM2 Cause Syndromic Urinary Tract Malformations.}, journal = {Am J Hum Genet}, volume = {107}, year = {2020}, month = {2020 10 01}, pages = {727-742}, abstract = {

Congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most frequent birth defects and represent the most common cause of chronic kidney disease in the first three decades of life. Despite the discovery of dozens of monogenic causes of CAKUT, most pathogenic pathways remain elusive. We performed whole-exome sequencing (WES) in 551 individuals with CAKUT and identified a heterozygous de novo stop-gain variant in ZMYM2 in two different families with CAKUT. Through collaboration, we identified in total 14 different heterozygous loss-of-function mutations in ZMYM2 in 15 unrelated families. Most mutations occurred de novo, indicating possible interference with reproductive function. Human disease features are replicated in X.~tropicalis larvae with morpholino knockdowns, in which expression of truncated ZMYM2 proteins, based on individual mutations, failed to rescue renal and craniofacial defects. Moreover, heterozygous Zmym2-deficient mice recapitulated features of CAKUT with high penetrance. The ZMYM2 protein is a component of a transcriptional corepressor complex recently linked to the silencing of developmentally regulated endogenous retrovirus elements. Using protein-protein interaction assays, we show that ZMYM2 interacts with additional epigenetic silencing complexes, as well as confirming that it binds to FOXP1, a transcription factor that has also been linked to CAKUT. In summary, our findings establish that loss-of-function mutations of ZMYM2, and potentially that of other proteins in its interactome, as causes of human CAKUT, offering new routes for studying the pathogenesis of the disorder.

}, keywords = {Amphibian Proteins, Animals, Case-Control Studies, Child, Child, Preschool, DNA-Binding Proteins, Epigenesis, Genetic, Family, Female, Forkhead Transcription Factors, Heterozygote, Humans, Infant, Larva, Male, Mice, Mice, Knockout, Morpholinos, Mutation, Pedigree, Protein Binding, Repressor Proteins, Transcription Factors, Urinary Tract, Urogenital Abnormalities, Whole Exome Sequencing, Xenopus}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2020.08.013}, author = {Connaughton, Dervla M and Dai, Rufeng and Owen, Danielle J and Marquez, Jonathan and Mann, Nina and GrAHm-Paquin, Adda L and Nakayama, Makiko and Coyaud, Etienne and Laurent, Estelle M N and St-Germain, Jonathan R and Blok, Lot Snijders and Vino, Arianna and Kl{\"a}mbt, Verena and Deutsch, Konstantin and Wu, Chen-Han Wilfred and Kolvenbach, Caroline M and Kause, Franziska and Ottlewski, Isabel and Schneider, Ronen and Kitzler, Thomas M and Majmundar, Amar J and Buerger, Florian and Onuchic-Whitford, Ana C and Youying, Mao and Kolb, Amy and Salmanullah, Daanya and Chen, Evan and van der Ven, Amelie T and Rao, Jia and Ityel, Hadas and Seltzsam, Steve and Rieke, Johanna M and Chen, Jing and Vivante, Asaf and Hwang, Daw-Yang and Kohl, Stefan and Dworschak, Gabriel C and Hermle, Tobias and Alders, Marielle and Bartolomaeus, Tobias and Bauer, Stuart B and Baum, Michelle A and Brilstra, Eva H and Challman, Thomas D and Zyskind, Jacob and Costin, Carrie E and Dipple, Katrina M and Duijkers, Floor A and Ferguson, Marcia and FitzPatrick, David R and Fick, Roger and Glass, Ian A and Hulick, Peter J and Kline, Antonie D and Krey, Ilona and Kumar, Selvin and Lu, Weining and Marco, Elysa J and Wentzensen, Ingrid M and Mefford, Heather C and Platzer, Konrad and Povolotskaya, Inna S and Savatt, Juliann M and Shcherbakova, Natalia V and Senguttuvan, Prabha and Squire, Audrey E and Stein, Deborah R and Thiffault, Isabelle and Voinova, Victoria Y and Somers, Michael J G and Ferguson, Michael A and Traum, Avram Z and Daouk, Ghaleb H and Daga, Ankana and Rodig, Nancy M and Terhal, Paulien A and van Binsbergen, Ellen and Eid, Loai A and Tasic, Velibor and Rasouly, Hila Milo and Lim, Tze Y and Ahram, Dina F and Gharavi, Ali G and Reutter, Heiko M and Rehm, Heidi L and MacArthur, Daniel G and Lek, Monkol and Laricchia, Kristen M and Lifton, Richard P and Xu, Hong and Mane, Shrikant M and Sanna-Cherchi, Simone and Sharrocks, Andrew D and Raught, Brian and Fisher, Simon E and Bouchard, Maxime and Khokha, Mustafa K and Shril, Shirlee and Hildebrandt, Friedhelm} } @article {799, title = {NEMF mutations that impair ribosome-associated quality control are associated with neuromuscular disease.}, journal = {Nat Commun}, volume = {11}, year = {2020}, month = {2020 09 15}, pages = {4625}, abstract = {

A hallmark of neurodegeneration is defective protein quality control. The E3 ligase Listerin (LTN1/Ltn1) acts in a specialized protein quality control pathway-Ribosome-associated Quality Control (RQC)-by mediating proteolytic targeting of incomplete polypeptides produced by ribosome stalling, and Ltn1 mutation leads to neurodegeneration in mice. Whether neurodegeneration results from defective RQC and whether defective RQC contributes to human disease have remained unknown. Here we show that three independently-generated mouse models with mutations in a different component of the RQC complex, NEMF/Rqc2, develop progressive motor neuron degeneration. Equivalent mutations in yeast Rqc2 selectively interfere with its ability to modify aberrant translation products with C-terminal tails which assist with RQC-mediated protein degradation, suggesting a pathomechanism. Finally, we identify NEMF mutations expected to interfere with function in patients from seven families presenting juvenile neuromuscular disease. These uncover NEMF{\textquoteright}s role in translational homeostasis in the nervous system and implicate RQC dysfunction in causing neurodegeneration.

}, keywords = {Amino Acid Sequence, Animals, Female, Humans, Male, Mice, Mice, Knockout, Mutation, Neuromuscular Diseases, Proteolysis, Ribosomes, RNA-Binding Proteins, Saccharomyces cerevisiae, Saccharomyces cerevisiae Proteins, Sequence Alignment}, issn = {2041-1723}, doi = {10.1038/s41467-020-18327-6}, author = {Martin, Paige B and Kigoshi-Tansho, Yu and Sher, Roger B and Ravenscroft, Gianina and Stauffer, Jennifer E and Kumar, Rajesh and Yonashiro, Ryo and M{\"u}ller, Tina and Griffith, Christopher and Allen, William and Pehlivan, Davut and Harel, Tamar and Zenker, Martin and Howting, Denise and Schanze, Denny and Faqeih, Eissa A and Almontashiri, Naif A M and Maroofian, Reza and Houlden, Henry and Mazaheri, Neda and Galehdari, Hamid and Douglas, Ganka and Posey, Jennifer E and Ryan, Monique and Lupski, James R and Laing, Nigel G and Joazeiro, Claudio A P and Cox, Gregory A} } @article {928, title = {Novel congenital disorder of O-linked glycosylation caused by GALNT2 loss of function.}, journal = {Brain}, volume = {143}, year = {2020}, month = {2020 04 01}, pages = {1114-1126}, abstract = {

Congenital disorders of glycosylation are a growing group of rare genetic disorders caused by deficient protein and lipid glycosylation. Here, we report the clinical, biochemical, and molecular features of seven patients from four families with GALNT2-congenital disorder of glycosylation (GALNT2-CDG), an O-linked glycosylation disorder. GALNT2 encodes the Golgi-localized polypeptide N-acetyl-d-galactosamine-transferase 2 isoenzyme. GALNT2 is widely expressed in most cell types and directs initiation of mucin-type protein O-glycosylation. All patients showed loss of O-glycosylation of apolipoprotein C-III, a non-redundant substrate for GALNT2. Patients with GALNT2-CDG generally exhibit a syndrome characterized by global developmental delay, intellectual disability with language deficit, autistic features, behavioural abnormalities, epilepsy, chronic insomnia, white matter changes on brain MRI, dysmorphic features, decreased stature, and decreased high density lipoprotein cholesterol levels. Rodent (mouse and rat) models of GALNT2-CDG recapitulated much of the human phenotype, including poor growth and neurodevelopmental abnormalities. In behavioural studies, GALNT2-CDG mice demonstrated cerebellar motor deficits, decreased sociability, and impaired sensory integration and processing. The multisystem nature of phenotypes in patients and rodent models of GALNT2-CDG suggest that there are multiple non-redundant protein substrates of GALNT2 in various tissues, including brain, which are critical to normal growth and development.

}, keywords = {Adolescent, Animals, Apolipoprotein C-III, Child, Child, Preschool, Developmental Disabilities, Female, Glycosylation, Humans, Loss of Function Mutation, Male, Mice, N-Acetylgalactosaminyltransferases, Pedigree, Rats, Young Adult}, issn = {1460-2156}, doi = {10.1093/brain/awaa063}, author = {Zilmer, Monica and Edmondson, Andrew C and Khetarpal, Sumeet A and Alesi, Viola and Zaki, MAH S and Rostasy, Kevin and Madsen, Camilla G and Lepri, Francesca R and Sinibaldi, Lorenzo and Cusmai, Raffaella and Novelli, Antonio and Issa, Mahmoud Y and Fenger, Christina D and Abou Jamra, Rami and Reutter, Heiko and Briuglia, Silvana and Agolini, Emanuele and Hansen, Lars and Pet{\"a}j{\"a}-Repo, Ulla E and Hintze, John and Raymond, Kimiyo M and Liedtke, Kristen and Stanley, Valentina and Musaev, Damir and Gleeson, Joseph G and Vitali, Cecilia and O{\textquoteright}Brien, W Timothy and Gardella, Elena and Rubboli, Guido and Rader, Daniel J and Schjoldager, Katrine T and M{\o}ller, Rikke S} } @article {910, title = {Pathogenic Variants in CEP85L Cause Sporadic and Familial Posterior Predominant Lissencephaly.}, journal = {Neuron}, volume = {106}, year = {2020}, month = {2020 04 22}, pages = {237-245.e8}, abstract = {

Lissencephaly (LIS), denoting a "smooth brain," is characterized by the absence of normal cerebral convolutions with abnormalities of cortical thickness. Pathogenic variants in over 20 genes are associated with LIS. The majority of posterior predominant LIS is caused by pathogenic variants in LIS1~(also known as PAFAH1B1), although a significant fraction remains without a known genetic etiology. We now implicate CEP85L as an important cause of~posterior predominant LIS, identifying 13 individuals with rare, heterozygous CEP85L variants, including 2 families with autosomal dominant inheritance. We show that CEP85L is a centrosome protein localizing to the pericentriolar material, and knockdown of Cep85l causes a neuronal migration defect in mice. LIS1 also localizes to the centrosome, suggesting that this organelle is key to the mechanism of posterior predominant LIS.

}, keywords = {Adolescent, Adult, Age of Onset, Animals, Centrosome, Child, Child, Preschool, Chromosome Aberrations, Classical Lissencephalies and Subcortical Band Heterotopias, Cytoskeletal Proteins, Female, Gene Knockdown Techniques, Genetic Variation, Heterozygote, Humans, Infant, Magnetic Resonance Imaging, Male, Mice, Mutation, Oncogene Proteins, Fusion, Pedigree, Seizures, Young Adult}, issn = {1097-4199}, doi = {10.1016/j.neuron.2020.01.027}, author = {Tsai, Meng-Han and Muir, Alison M and Wang, Won-Jing and Kang, Yi-Ning and Yang, Kun-Chuan and Chao, Nian-Hsin and Wu, Mei-Feng and Chang, Ying-Chao and Porter, Brenda E and Jansen, Laura A and Sebire, Guillaume and Deconinck, Nicolas and Fan, Wen-Lang and Su, Shih-Chi and Chung, Wen-Hung and Almanza Fuerte, Edith P and Mehaffey, Michele G and Ng, Ching-Ching and Chan, Chung-Kin and Lim, Kheng-Seang and Leventer, Richard J and Lockhart, Paul J and Riney, Kate and Damiano, John A and Hildebrand, Michael S and Mirzaa, Ghayda M and Dobyns, William B and Berkovic, Samuel F and Scheffer, Ingrid E and Tsai, Jin-Wu and Mefford, Heather C} } @article {746, title = {Regulation of human cerebral cortical development by EXOC7 and EXOC8, components of the exocyst complex, and roles in neural progenitor cell proliferation and survival.}, journal = {Genet Med}, volume = {22}, year = {2020}, month = {2020 06}, pages = {1040-1050}, abstract = {

PURPOSE: The exocyst complex is a conserved protein complex that mediates fusion of intracellular vesicles to the plasma membrane and is implicated in processes including cell polarity, cell migration, ciliogenesis, cytokinesis, autophagy, and fusion of secretory vesicles. The essential role of these genes in human genetic disorders, however, is unknown.

METHODS: We performed homozygosity mapping and exome sequencing of consanguineous families with recessively inherited brain development disorders. We modeled an EXOC7 splice variant in vitro and examined EXOC7 messenger RNA (mRNA) expression in developing mouse and human cortex. We modeled exoc7 loss-of-function in a zebrafish knockout.

RESULTS: We report variants in exocyst complex members, EXOC7 and EXOC8, in a novel disorder of cerebral cortex development. In EXOC7, we identified four independent partial loss-of-function (LOF) variants in a recessively inherited disorder characterized by brain atrophy, seizures, and developmental delay, and in severe cases, microcephaly and infantile death. In EXOC8, we found a homozygous truncating variant in a family with a similar clinical disorder. We modeled exoc7 deficiency in zebrafish and found the absence of exoc7 causes microcephaly.

CONCLUSION: Our results highlight the essential role of the exocyst pathway in normal cortical development and how its perturbation causes complex brain disorders.

}, keywords = {Animals, Brain Diseases, Cell Proliferation, Homozygote, Humans, Mice, Microcephaly, Zebrafish}, issn = {1530-0366}, doi = {10.1038/s41436-020-0758-9}, author = {Coulter, Michael E and Musaev, Damir and DeGennaro, Ellen M and Zhang, Xiaochang and Henke, Katrin and James, Kiely N and Smith, Richard S and Hill, R Sean and Partlow, Jennifer N and Kamumbu, A Stacy and Hatem, Nicole and Barkovich, A James and Aziza, Jacqueline and Chassaing, Nicolas and Zaki, MAH S and Sultan, Tipu and Burglen, Lydie and Rajab, Anna and Al-Gazali, Lihadh and Mochida, Ganeshwaran H and Harris, Matthew P and Gleeson, Joseph G and Walsh, Christopher A} } @article {820, title = {Tyrosyl phosphorylation of PZR promotes hypertrophic cardiomyopathy in PTPN11-associated Noonan syndrome with multiple lentigines.}, journal = {JCI Insight}, volume = {5}, year = {2020}, month = {2020 08 06}, abstract = {

Noonan syndrome with multiple lentigines (NSML) is a rare autosomal dominant disorder that presents with cardio-cutaneous-craniofacial defects. Hypertrophic cardiomyopathy (HCM) represents the major life-threatening presentation in NSML. Mutations in the PTPN11 gene that encodes for the protein tyrosine phosphatase (PTP), SHP2, represents the predominant cause of HCM in NSML. NSML-associated PTPN11 mutations render SHP2 catalytically inactive with an "open" conformation. NSML-associated PTPN11 mutations cause hypertyrosyl phosphorylation of the transmembrane glycoprotein, protein zero-related (PZR), resulting in increased SHP2 binding. Here we show that NSML mice harboring a tyrosyl phosphorylation-defective mutant of PZR (NSML/PZRY242F) that is defective for SHP2 binding fail to develop HCM. Enhanced AKT/S6 kinase signaling in heart lysates of NSML mice was reversed in NSML/PZRY242F mice, demonstrating that PZR/SHP2 interactions promote aberrant AKT/S6 kinase activity in NSML. Enhanced PZR tyrosyl phosphorylation in the hearts of NSML mice was found to drive myocardial fibrosis by engaging an Src/NF-κB pathway, resulting in increased activation of IL-6. Increased expression of IL-6 in the hearts of NSML mice was reversed in NSML/PZRY242F mice, and PZRY242F mutant fibroblasts were defective for IL-6 secretion and STAT3-mediated fibrogenesis. These results demonstrate that NSML-associated PTPN11 mutations that induce PZR hypertyrosyl phosphorylation trigger pathophysiological signaling that promotes HCM and cardiac fibrosis.

}, keywords = {Animals, Cardiomyopathy, Hypertrophic, Disease Models, Animal, Female, Intracellular Signaling Peptides and Proteins, LEOPARD Syndrome, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutation, Myocytes, Cardiac, Phosphoproteins, Phosphorylation, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Tyrosine}, issn = {2379-3708}, doi = {10.1172/jci.insight.137753}, author = {Yi, Jae-Sung and Perla, Sravan and Enyenihi, Liz and Bennett, Anton M} } @article {583, title = {Lack of GAS2L2 Causes PCD by Impairing Cilia Orientation and Mucociliary Clearance.}, journal = {Am J Hum Genet}, volume = {104}, year = {2019}, month = {2019 02 07}, pages = {229-245}, abstract = {

Primary ciliary dyskinesia (PCD) is a genetic disorder in which impaired ciliary function leads to chronic airway disease. Exome sequencing of a PCD subject identified an apparent homozygous frameshift variant, c.887_890delTAAG (p.Val296Glyfs13), in exon 5; this frameshift introduces a stop codon in amino acid 308 of the growth arrest-specific protein 2-like 2 (GAS2L2). Further genetic screening of unrelated PCD subjects identified a second proband with a compound heterozygous variant carrying the identical frameshift variant and a large deletion (c.867_343+1207del; p.?) starting in exon 5. Both individuals had clinical features of PCD but normal ciliary axoneme structure. In this research, using human nasal cells, mouse models, and X.laevis embryos, we show that GAS2L2 is abundant at the apical surface of ciliated cells, where it localizes with basal bodies, basal feet, rootlets, and actin filaments. Cultured GAS2L2-deficient nasal epithelial cells from one of the affected individuals showed defects in ciliary orientation and had an asynchronous and hyperkinetic (GAS2L2-deficient = 19.8~Hz versus control = 15.8~Hz) ciliary-beat pattern. These results were recapitulated in Gas2l2 mouse tracheal epithelial cell (mTEC) cultures and in X.~laevis embryos treated with Gas2l2 morpholinos. In mice, the absence of Gas2l2 caused neonatal death, and the conditional deletion of Gas2l2 impaired mucociliary clearance (MCC) and led to mucus accumulation. These results show that a pathogenic variant in GAS2L2 causes a genetic defect in ciliary orientation and impairs MCC and results in~PCD.

}, keywords = {Animals, Cilia, Ciliary Motility Disorders, Disease Models, Animal, Exons, Female, Gene Deletion, Genes, Lethal, Humans, Male, Mice, Mice, Knockout, Microfilament Proteins, Microtubule-Associated Proteins, Phenotype, Rotation, Xenopus}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.12.009}, author = {Bustamante-Marin, Ximena M and Yin, Wei-Ning and Sears, Patrick R and Werner, Michael E and Brotslaw, Eva J and Mitchell, Brian J and Jania, Corey M and Zeman, Kirby L and Rogers, Troy D and Herring, Laura E and Refab{\'e}rt, Luc and Thomas, Lucie and Amselem, Serge and Escudier, Estelle and Legendre, Marie and Grubb, Barbara R and Knowles, Michael R and Zariwala, Maimoona A and Ostrowski, Lawrence E} } @article {566, title = {ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm.}, journal = {Nat Genet}, volume = {51}, year = {2019}, month = {2019 01}, pages = {42-50}, abstract = {

Bicuspid aortic valve (BAV) is a common congenital heart defect (population incidence, 1-2\%) that frequently presents with ascending aortic aneurysm (AscAA). BAV/AscAA shows autosomal dominant inheritance with incomplete penetrance and male predominance. Causative gene mutations (for example, NOTCH1, SMAD6) are known for <=1\% of nonsyndromic BAV cases with and without AscAA, impeding mechanistic insight and development of therapeutic strategies. Here, we report the identification of variants in ROBO4 (which encodes a factor known to contribute to endothelial performance) that segregate with disease in two families. Targeted sequencing of ROBO4 showed enrichment for rare variants in BAV/AscAA probands compared with controls. Targeted silencing of ROBO4 or mutant ROBO4 expression in endothelial cell lines results in impaired barrier function and a synthetic repertoire suggestive of endothelial-to-mesenchymal transition. This is consistent with BAV/AscAA-associated findings in patients and in animal models deficient for ROBO4. These data identify a novel endothelial etiology for this common human disease phenotype.

}, keywords = {Animals, Aortic Aneurysm, Thoracic, Aortic Valve, Cells, Cultured, Disease Models, Animal, Endothelial Cells, Female, Heart Valve Diseases, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutation, Phenotype, Receptors, Cell Surface, Zebrafish}, issn = {1546-1718}, doi = {10.1038/s41588-018-0265-y}, author = {Gould, Russell A and Aziz, Hamza and Woods, Courtney E and Seman-Senderos, Manuel Alejandro and Sparks, Elizabeth and Preuss, Christoph and W{\"u}nnemann, Florian and Bedja, Djahida and Moats, Cassandra R and McClymont, Sarah A and Rose, Rebecca and Sobreira, Nara and Ling, Hua and MacCarrick, Gretchen and Kumar, Ajay Anand and Luyckx, Ilse and Cannaerts, Elyssa and Verstraeten, Aline and Bj{\"o}rk, Hanna M and Lehsau, Ann-Cathrin and Jaskula-Ranga, Vinod and Lauridsen, Henrik and Shah, Asad A and Bennett, Christopher L and Ellinor, Patrick T and Lin, Honghuang and Isselbacher, Eric M and Lino Cardenas, Christian Lacks and Butcher, Jonathan T and Hughes, G Chad and Lindsay, Mark E and Mertens, Luc and Franco-Cereceda, Anders and Verhagen, Judith M A and Wessels, Marja and Mohamed, Salah A and Eriksson, Per and Mital, Seema and Van Laer, Lut and Loeys, Bart L and Andelfinger, Gregor and McCallion, Andrew S and Dietz, Harry C} } @article {570, title = {TBX6 compound inheritance leads to congenital vertebral malformations in humans and mice.}, journal = {Hum Mol Genet}, volume = {28}, year = {2019}, month = {2019 02 15}, pages = {539-547}, abstract = {

Congenital vertebral malformations (CVMs) are associated with human TBX6 compound inheritance that combines a rare null allele and a common hypomorphic allele at the TBX6 locus. Our previous in vitro evidence suggested that this compound inheritance resulted in a TBX6 gene dosage of less than haploinsufficiency (i.e. <50\%) as a potential mechanism of TBX6-associated CVMs. To further investigate this pathogenetic model, we ascertained and collected 108 Chinese CVM cases and found that 10 (9.3\%) of them carried TBX6 null mutations in combination with common hypomorphic variants at the second TBX6 allele. For in vivo functional verification and genetic analysis of TBX6 compound inheritance, we generated both null and hypomorphic mutations in mouse Tbx6 using the CRISPR-Cas9 method. These Tbx6 mutants are not identical to the patient variants at the DNA sequence level, but instead functionally mimic disease-associated TBX6 variants. Intriguingly, as anticipated by the compound inheritance model, a high penetrance of CVM phenotype was only observed in the mice with combined null and hypomorphic alleles of Tbx6. These findings are consistent with our experimental observations in humans and supported the dosage effect of TBX6 in CVM etiology. In conclusion, our findings in the newly collected human CVM subjects and Tbx6 mouse models consistently support the contention that TBX6 compound inheritance causes CVMs, potentially via a gene dosage-dependent mechanism. Furthermore, mouse Tbx6 mutants mimicking human CVM-associated variants will be useful models for further mechanistic investigations of CVM pathogenesis in the cases associated with TBX6.

}, keywords = {Adolescent, Alleles, Animals, Child, Child, Preschool, Congenital Abnormalities, CRISPR-Cas Systems, Disease Models, Animal, Female, Haploinsufficiency, Humans, Infant, Male, Mice, Mutation, Phenotype, Scoliosis, Spine, T-Box Domain Proteins}, issn = {1460-2083}, doi = {10.1093/hmg/ddy358}, author = {Yang, Nan and Wu, Nan and Zhang, Ling and Zhao, Yanxue and Liu, Jiaqi and Liang, Xiangyu and Ren, Xiaojun and Li, Weiyu and Chen, Weisheng and Dong, Shuangshuang and Zhao, Sen and Lin, Jiachen and Xiang, Hang and Xue, Huadan and Chen, Lu and Sun, Hao and Zhang, Jianguo and Shi, Jiangang and Zhang, Shuyang and Lu, Daru and Wu, Xiaohui and Jin, Li and Ding, Jiandong and Qiu, Guixing and Wu, Zhihong and Lupski, James R and Zhang, Feng} } @article {577, title = {ZMIZ1 Variants Cause a Syndromic Neurodevelopmental Disorder.}, journal = {Am J Hum Genet}, volume = {104}, year = {2019}, month = {2019 02 07}, pages = {319-330}, abstract = {

ZMIZ1 is a coactivator of several transcription factors, including p53, the androgen receptor, and NOTCH1. Here, we report 19 subjects with intellectual disability and developmental delay carrying variants in ZMIZ1. The associated features include growth failure, feeding difficulties, microcephaly, facial dysmorphism, and various other congenital malformations. Of these 19, 14 unrelated subjects carried de~novo heterozygous single-nucleotide variants (SNVs) or single-base insertions/deletions, 3 siblings harbored a heterozygous single-base insertion, and 2 subjects had a balanced translocation disrupting ZMIZ1 or involving a regulatory region of ZMIZ1. In total, we identified 13 point mutations that affect key protein regions, including a SUMO acceptor site, a central disordered alanine-rich motif, a proline-rich domain, and a transactivation domain. All identified variants were absent from all available exome and genome databases. In~vitro, ZMIZ1 showed impaired coactivation of the androgen receptor. In~vivo, overexpression of ZMIZ1 mutant alleles in developing mouse brains using in utero electroporation resulted in abnormal pyramidal neuron morphology, polarization, and positioning, underscoring the importance of ZMIZ1 in neural development and supporting mutations in ZMIZ1 as the cause of a rare neurodevelopmental syndrome.

}, keywords = {Alleles, Animals, Child, Child, Preschool, Developmental Disabilities, Female, Humans, Infant, Intellectual Disability, Male, Mice, Point Mutation, Syndrome, Transcription Factors}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.12.007}, author = {Carapito, Raphael and Ivanova, Ekaterina L and Morlon, Aurore and Meng, Linyan and Molitor, Anne and Erdmann, Eva and Kieffer, Bruno and Pichot, Ang{\'e}lique and Naegely, Lydie and Kolmer, Aline and Paul, Nicod{\`e}me and Hanauer, Antoine and Tran Mau-Them, Fr{\'e}d{\'e}ric and Jean-Mar{\c c}ais, Nolwenn and Hiatt, Susan M and Cooper, Gregory M and Tvrdik, Tatiana and Muir, Alison M and Dimartino, Cl{\'e}mantine and Chopra, Maya and Amiel, Jeanne and Gordon, Christopher T and Dutreux, Fabien and Garde, Aurore and Thauvin-Robinet, Christel and Wang, Xia and Leduc, Magalie S and Phillips, Meredith and Crawford, Heather P and Kukolich, Mary K and Hunt, David and Harrison, Victoria and Kharbanda, Mira and Smigiel, Robert and Gold, Nina and Hung, Christina Y and Viskochil, David H and Dugan, Sarah L and Bayrak-Toydemir, Pinar and Joly-Helas, G{\'e}raldine and Guerrot, Anne-Marie and Schluth-Bolard, Caroline and Rio, Marl{\`e}ne and Wentzensen, Ingrid M and McWalter, Kirsty and Schnur, Rhonda E and Lewis, Andrea M and Lalani, Seema R and Mensah-Bonsu, No{\"e}l and C{\'e}raline, Jocelyn and Sun, Zijie and Ploski, Rafal and Bacino, Carlos A and Mefford, Heather C and Faivre, Laurence and Bodamer, Olaf and Chelly, Jamel and Isidor, Bertrand and Bahram, Seiamak} } @article {466, title = {A biallelic ANTXR1 variant expands the anthrax toxin receptor associated phenotype to tooth agenesis.}, journal = {Am J Med Genet A}, volume = {176}, year = {2018}, month = {2018 04}, pages = {1015-1022}, abstract = {

Tooth development is regulated by multiple genetic pathways, which ultimately drive the complex interactions between the oral epithelium and mesenchyme. Disruptions at any time point during this process may lead to failure of tooth development, also known as tooth agenesis (TA). TA is a common craniofacial abnormality in humans and represents the failure to develop one or more permanent teeth. Many genes and potentially subtle variants in these genes contribute to the TA phenotype. We report the clinical and genetic impact of a rare homozygous ANTXR1 variant (c.1312C>T), identified by whole exome sequencing (WES), in a consanguineous Turkish family with TA. Mutations in ANTXR1 have been associated with GAPO (growth retardation, alopecia, pseudoanodontia, and optic atrophy) syndrome and infantile hemangioma, however no clinical characteristics associated with these conditions were observed in our study family. We detected the expression of Antxr1 in oral and dental tissues of developing mouse embryos, further supporting a role for this gene in tooth development. Our findings implicate ANTXR1 as a candidate gene for isolated TA, suggest the involvement of specific hypomorphic alleles, and expand the previously known ANTXR1-associated phenotypes.

}, keywords = {Alleles, Amino Acid Substitution, Animals, Anodontia, Child, Consanguinity, Facies, Genetic Association Studies, Genotype, Humans, Male, Mice, Mutation, Neoplasm Proteins, Pedigree, Phenotype, Radiography, Receptors, Cell Surface, Whole Exome Sequencing}, issn = {1552-4833}, doi = {10.1002/ajmg.a.38625}, author = {Dinckan, Nuriye and Du, Renqian and Akdemir, Zeynep C and Bayram, Yavuz and Jhangiani, Shalini N and Doddapaneni, Harsha and Hu, Jianhong and Muzny, Donna M and Guven, Yeliz and Aktoren, Oya and Kayserili, H{\"u}lya and Boerwinkle, Eric and Gibbs, Richard A and Posey, Jennifer E and Lupski, James R and Uyguner, Zehra O and Letra, Ariadne} } @article {545, title = {A homozygous missense variant in VWA2, encoding an interactor of the Fraser-complex, in a patient with vesicoureteral reflux.}, journal = {PLoS One}, volume = {13}, year = {2018}, month = {2018}, pages = {e0191224}, abstract = {

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause (40-50\%) of chronic kidney disease (CKD) in children. About 40 monogenic causes of CAKUT have so far been discovered. To date less than 20\% of CAKUT cases can be explained by mutations in these 40 genes. To identify additional monogenic causes of CAKUT, we performed whole exome sequencing (WES) and homozygosity mapping (HM) in a patient with CAKUT from Indian origin and consanguineous descent. We identified a homozygous missense mutation (c.1336C>T, p.Arg446Cys) in the gene Von Willebrand factor A domain containing 2 (VWA2). With immunohistochemistry studies on kidneys of newborn (P1) mice, we show that Vwa2 and Fraser extracellular matrix complex subunit 1 (Fras1) co-localize in the nephrogenic zone of the renal cortex. We identified a pronounced expression of Vwa2 in the basement membrane of the ureteric bud (UB) and derivatives of the metanephric mesenchyme (MM). By applying in vitro assays, we demonstrate that the Arg446Cys mutation decreases translocation of monomeric VWA2 protein and increases translocation of aggregated VWA2 protein into the extracellular space. This is potentially due to the additional, unpaired cysteine residue in the mutated protein that is used for intermolecular disulfide bond formation. VWA2 is a known, direct interactor of FRAS1 of the Fraser-Complex (FC). FC-encoding genes and interacting proteins have previously been implicated in the pathogenesis of syndromic and/or isolated CAKUT phenotypes in humans. VWA2 therefore constitutes a very strong candidate in the search for novel CAKUT-causing genes. Our results from in vitro experiments indicate a dose-dependent neomorphic effect of the Arg446Cys homozygous mutation in VWA2.

}, keywords = {Amino Acid Sequence, Amino Acid Substitution, Animals, Animals, Newborn, Biomarkers, Tumor, Child, Consanguinity, Conserved Sequence, Exons, Extracellular Matrix Proteins, Fraser Syndrome, Gene Expression Regulation, Developmental, Homozygote, Humans, Male, Mice, Models, Animal, Models, Molecular, Mutation, Missense, Pedigree, Sequence Homology, Amino Acid, Urogenital Abnormalities, Urogenital System, Vesico-Ureteral Reflux}, issn = {1932-6203}, doi = {10.1371/journal.pone.0191224}, author = {van der Ven, Amelie T and Kobbe, Birgit and Kohl, Stefan and Shril, Shirlee and Pogoda, Hans-Martin and Imhof, Thomas and Ityel, Hadas and Vivante, Asaf and Chen, Jing and Hwang, Daw-Yang and Connaughton, Dervla M and Mann, Nina and Widmeier, Eugen and Taglienti, Mary and Schmidt, Johanna Magdalena and Nakayama, Makiko and Senguttuvan, Prabha and Kumar, Selvin and Tasic, Velibor and Kehinde, Elijah O and Mane, Shrikant M and Lifton, Richard P and Soliman, Neveen and Lu, Weining and Bauer, Stuart B and Hammerschmidt, Matthias and Wagener, Raimund and Hildebrandt, Friedhelm} } @article {626, title = {LTBP3 Pathogenic Variants Predispose Individuals to Thoracic Aortic Aneurysms and Dissections.}, journal = {Am J Hum Genet}, volume = {102}, year = {2018}, month = {2018 04 05}, pages = {706-712}, abstract = {

The major diseases affecting the thoracic aorta are aneurysms and acute dissections, and pathogenic variants in 11 genes are confirmed to lead to heritable thoracic aortic disease. However, many families in which multiple members have thoracic aortic disease do not have alterations in the known aortopathy genes. Genes highly expressed in the aorta were assessed for rare variants in exome sequencing data from such families, and compound rare heterozygous variants (p.Pro45Argfs25 and p.Glu750) in LTBP3 were identified in affected members of one family. A homozygous variant (p.Asn678_Gly681delinsThrCys) that introduces an additional cysteine into an epidermal growth factor (EGF)-like domain in the corresponding protein, latent TGF-β binding protein (LTBP-3), was identified in a second family. Individuals with compound heterozygous or homozygous variants in these families have aneurysms and dissections of the thoracic aorta, as well as aneurysms of the abdominal aorta and other arteries, along with dental abnormalities and short stature. Heterozygous carriers of the p.Asn678_Gly681delinsThrCys variant have later onset of thoracic aortic disease, as well as dental abnormalities. In these families, LTBP3 variants segregated with thoracic aortic disease with a combined LOD score of 3.9. Additionally, heterozygous rare LTBP3 variants were found in individuals with early onset of acute aortic dissections, and some of these variants disrupted LTBP-3 levels or EGF-like domains. When compared to wild-type mice, Ltbp3 mice have enlarged aortic roots and ascending aortas. In summary, homozygous LTBP3 pathogenic variants predispose individuals to thoracic aortic aneurysms and dissections, along with the previously described skeletal and dental abnormalities.

}, keywords = {Adult, Aged, 80 and over, Aneurysm, Dissecting, Animals, Aortic Aneurysm, Thoracic, Blood Pressure, Female, Genetic Predisposition to Disease, Homozygote, Humans, Latent TGF-beta Binding Proteins, Male, Mice, Middle Aged, Mutation, Pedigree}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.03.002}, author = {Guo, Dong-Chuan and Regalado, Ellen S and Pinard, Amelie and Chen, Jiyuan and Lee, Kwanghyuk and Rigelsky, Christina and Zilberberg, Lior and Hostetler, Ellen M and Aldred, Micheala and Wallace, Stephanie E and Prakash, Siddharth K and Leal, Suzanne M and Bamshad, Michael J and Nickerson, Deborah A and Natowicz, Marvin and Rifkin, Daniel B and Milewicz, Dianna M} } @article {615, title = {Mutation in the intracellular chloride channel CLCC1 associated with autosomal recessive retinitis pigmentosa.}, journal = {PLoS Genet}, volume = {14}, year = {2018}, month = {2018 08}, pages = {e1007504}, abstract = {

We identified a homozygous missense alteration (c.75C>A, p.D25E) in CLCC1, encoding a presumptive intracellular chloride channel highly expressed in the retina, associated with autosomal recessive retinitis pigmentosa (arRP) in eight consanguineous families of Pakistani descent. The p.D25E alteration decreased CLCC1 channel function accompanied by accumulation of mutant protein in granules within the ER lumen, while siRNA knockdown of CLCC1 mRNA induced apoptosis in cultured ARPE-19 cells. TALEN KO in zebrafish was lethal 11 days post fertilization. The depressed electroretinogram (ERG) cone response and cone spectral sensitivity of 5 dpf KO zebrafish and reduced eye size, retinal thickness, and expression of rod and cone opsins could be rescued by injection of wild type CLCC1 mRNA. Clcc1+/- KO mice showed decreased ERGs and photoreceptor number. Together these results strongly suggest that intracellular chloride transport by CLCC1 is a critical process in maintaining retinal integrity, and CLCC1 is crucial for survival and function of retinal cells.

}, keywords = {Animals, Asian Continental Ancestry Group, Cell Line, Chloride Channels, Cytoplasm, Eye Proteins, HEK293 Cells, Homozygote, Humans, Mice, Mice, Knockout, Mutation, Missense, Pakistan, Retina, Retinal Cone Photoreceptor Cells, Retinal Rod Photoreceptor Cells, Retinitis Pigmentosa, Zebrafish}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1007504}, author = {Li, Lin and Jiao, Xiaodong and D{\textquoteright}Atri, Ilaria and Ono, Fumihito and Nelson, Ralph and Chan, Chi-Chao and Nakaya, Naoki and Ma, Zhiwei and Ma, Yan and Cai, Xiaoying and Zhang, Longhua and Lin, Siying and Hameed, Abdul and Chioza, Barry A and Hardy, Holly and Arno, Gavin and Hull, Sarah and Khan, Muhammad Imran and Fasham, James and Harlalka, Gaurav V and Michaelides, Michel and Moore, Anthony T and Coban Akdemir, Zeynep Hande and Jhangiani, Shalini and Lupski, James R and Cremers, Frans P M and Qamar, Raheel and Salman, Ahmed and Chilton, John and Self, Jay and Ayyagari, Radha and Kabir, Firoz and Naeem, Muhammad Asif and Ali, Muhammad and Akram, Javed and Sieving, Paul A and Riazuddin, Sheikh and Baple, Emma L and Riazuddin, S Amer and Crosby, Andrew H and Hejtmancik, J Fielding} } @article {474, title = {Mutations in the Epithelial Cadherin-p120-Catenin Complex Cause Mendelian Non-Syndromic Cleft Lip with or without Cleft Palate.}, journal = {Am J Hum Genet}, volume = {102}, year = {2018}, month = {2018 06 07}, pages = {1143-1157}, abstract = {

Non-syndromic cleft lip with or without cleft palate (NS-CL/P) is one of the most common human birth defects and is generally considered a complex trait. Despite numerous loci identified by genome-wide association studies, the effect sizes of common variants are relatively small, with much of the presumed genetic contribution remaining elusive. We report exome-sequencing results in 209 people from 72 multi-affected families with pedigree structures consistent with autosomal-dominant inheritance and variable penetrance. Herein, pathogenic variants are described in four genes encoding components of the p120-catenin complex (CTNND1, PLEKHA7, PLEKHA5) and an epithelial splicing regulator (ESRP2), in addition to the known CL/P-associated gene, CDH1, which encodes E-cadherin. The findings were also validated in a second cohort of 497 people with NS-CL/P, comprising small families and singletons with pathogenic variants in these genes identified in 14\% of multi-affected families and 2\% of the replication cohort of smaller families. Enriched expression of each gene/protein in human and mouse embryonic oro-palatal epithelia, demonstration of functional impact of CTNND1 and ESRP2 variants, and recapitulation of the CL/P spectrum in Ctnnd1 knockout mice support a causative role in CL/P pathogenesis. These data show that primary defects in regulators of epithelial cell adhesion are the most significant contributors to NS-CL/P identified to date and that inherited and de novo single gene variants explain a substantial proportion of NS-CL/P.

}, keywords = {Alleles, Amino Acid Sequence, Animals, Biotinylation, Cadherins, Catenins, Cleft Lip, Cleft Palate, Epithelium, Female, Gene Deletion, Genetic Predisposition to Disease, Humans, Infant, Infant, Newborn, Male, Mice, Mutation, Palate, Pedigree, Syndrome, Whole Exome Sequencing}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.04.009}, author = {Cox, Liza L and Cox, Timothy C and Moreno Uribe, Lina M and Zhu, Ying and Richter, Chika T and Nidey, Nichole and Standley, Jennifer M and Deng, Mei and Blue, Elizabeth and Chong, Jessica X and Yang, Yueqin and Carstens, Russ P and Anand, Deepti and Lachke, Salil A and Smith, Joshua D and Dorschner, Michael O and Bedell, Bruce and Kirk, Edwin and Hing, Anne V and Venselaar, Hanka and Valencia-Ramirez, Luz C and Bamshad, Michael J and Glass, Ian A and Cooper, Jonathan A and Haan, Eric and Nickerson, Deborah A and van Bokhoven, Hans and Zhou, Huiqing and Krahn, Katy N and Buckley, Michael F and Murray, Jeffrey C and Lidral, Andrew C and Roscioli, Tony} } @article {465, title = {The role of FREM2 and FRAS1 in the development of congenital diaphragmatic hernia.}, journal = {Hum Mol Genet}, volume = {27}, year = {2018}, month = {2018 06 15}, pages = {2064-2075}, abstract = {

Congenital diaphragmatic hernia (CDH) has been reported twice in individuals with a clinical diagnosis of Fraser syndrome, a genetic disorder that can be caused by recessive mutations affecting FREM2 and FRAS1. In the extracellular matrix, FREM2 and FRAS1 form a self-stabilizing complex with FREM1, a protein whose deficiency causes sac CDH in humans and mice. By sequencing FREM2 and FRAS1 in a CDH cohort, and searching online databases, we identified five individuals who carried recessive or double heterozygous, putatively deleterious variants in these genes which may represent susceptibility alleles. Three of these alleles were significantly enriched in our CDH cohort compared with ethnically matched controls. We subsequently demonstrated that 8\% of Frem2ne/ne and 1\% of Fras1Q1263*/Q1263* mice develop the same type of anterior sac CDH seen in FREM1-deficient mice. We went on to show that development of sac hernias in FREM1-deficient mice is preceded by failure of anterior mesothelial fold progression resulting in the persistence of an amuscular, poorly vascularized anterior diaphragm that is abnormally adherent to the underlying liver. Herniation occurs in the perinatal period when the expanding liver protrudes through this amuscular region of the anterior diaphragm that is juxtaposed to areas of muscular diaphragm. Based on these data, we conclude that deficiency of FREM2, and possibly FRAS1, are associated with an increased risk of developing CDH and that loss of the FREM1/FREM2/FRAS1 complex, or its function, leads to anterior sac CDH development through its effects on mesothelial fold progression.

}, keywords = {Animals, Child, Child, Preschool, Epithelium, Extracellular Matrix Proteins, Female, Hernias, Diaphragmatic, Congenital, Humans, Infant, Infant, Newborn, Male, Mice, Mice, Knockout, Mutation, Pregnancy, Receptors, Interleukin}, issn = {1460-2083}, doi = {10.1093/hmg/ddy110}, author = {Jordan, Valerie K and Beck, Tyler F and Hernandez-Garcia, Andres and Kundert, Peter N and Kim, Bum-Jun and Jhangiani, Shalini N and Gambin, Tomasz and Starkovich, Molly and Punetha, Jaya and Paine, Ingrid S and Posey, Jennifer E and Li, Alexander H and Muzny, Donna and Hsu, Chih-Wei and Lashua, Amber J and Sun, Xin and Fernandes, Caraciolo J and Dickinson, Mary E and Lally, Kevin P and Gibbs, Richard A and Boerwinkle, Eric and Lupski, James R and Scott, Daryl A} } @article {485, title = {A variant in LMX1A causes autosomal recessive severe-to-profound hearing impairment.}, journal = {Hum Genet}, volume = {137}, year = {2018}, month = {2018 Jul}, pages = {471-478}, abstract = {

Hereditary hearing impairment is a common sensory disorder that is genetically and phenotypically heterogeneous. In this study, we used a homozygosity mapping and exome sequencing strategy to study a consanguineous Pakistani family with autosomal recessive severe-to-profound hearing impairment. This led to the identification of a missense variant (p.Ile369Thr) in the LMX1A gene affecting a conserved residue in the C-terminus of the protein, which was predicted damaging by an in silico bioinformatics analysis. The p.Ile369Thr variant disrupts several C-terminal and homeodomain residue interactions, including an interaction with homeodomain residue p.Val241 that was previously found to be involved in autosomal dominant progressive HI. LIM-homeodomain factor Lmx1a is expressed in the inner ear through development, shows a progressive restriction to non-sensory epithelia, and is important in the separation of the sensory and non-sensory domains in the inner ear. Homozygous Lmx1a mutant mice (Dreher) are deaf with dysmorphic ears with an abnormal morphogenesis and fused and misshapen sensory organs; however, computed tomography performed on a hearing-impaired family member did not reveal any cochleovestibular malformations. Our results suggest that LMX1A is involved in both human autosomal recessive and dominant sensorineural hearing impairment.

}, keywords = {Adolescent, Adult, Animals, Child, Disease Models, Animal, Ear, Inner, Female, Genes, Dominant, Genes, Recessive, Hearing Loss, Hearing Loss, Sensorineural, Homozygote, Humans, LIM-Homeodomain Proteins, Male, Mice, Mutation, Missense, Pedigree, Transcription Factors, Whole Exome Sequencing}, issn = {1432-1203}, doi = {10.1007/s00439-018-1899-7}, author = {Schrauwen, Isabelle and Chakchouk, Imen and Liaqat, Khurram and Jan, Abid and Nasir, Abdul and Hussain, Shabir and Nickerson, Deborah A and Bamshad, Michael J and Ullah, Asmat and Ahmad, Wasim and Leal, Suzanne M} } @article {437, title = {Asprosin is a centrally acting orexigenic hormone.}, journal = {Nat Med}, volume = {23}, year = {2017}, month = {2017 Dec}, pages = {1444-1453}, abstract = {

Asprosin is a recently discovered fasting-induced hormone that promotes hepatic glucose production. Here we demonstrate that asprosin in the circulation crosses the blood-brain barrier and directly activates orexigenic AgRP neurons via a cAMP-dependent pathway. This signaling results in inhibition of downstream anorexigenic proopiomelanocortin (POMC)-positive neurons in a GABA-dependent manner, which then leads to appetite stimulation and a drive to accumulate adiposity and body weight. In humans, a genetic deficiency in asprosin causes a syndrome characterized by low appetite and extreme leanness; this is phenocopied by mice carrying similar mutations and can be fully rescued by asprosin. Furthermore, we found that obese humans and mice had pathologically elevated concentrations of circulating asprosin, and neutralization of asprosin in the blood with a monoclonal antibody reduced appetite and body weight in obese mice, in addition to improving their glycemic profile. Thus, in addition to performing a glucogenic function, asprosin is a centrally acting orexigenic hormone that is a potential therapeutic target in the treatment of both obesity and diabetes.

}, keywords = {Adolescent, Adult, Animals, Appetite Depressants, Appetite Regulation, Female, Humans, Hypothalamus, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microfilament Proteins, Neurons, Peptide Fragments, Peptide Hormones, Rats, Signal Transduction, Young Adult}, issn = {1546-170X}, doi = {10.1038/nm.4432}, author = {Duerrschmid, Clemens and He, Yanlin and Wang, Chunmei and Li, Chia and Bournat, Juan C and Romere, Chase and Saha, Pradip K and Lee, Mark E and Phillips, Kevin J and Jain, Mahim and Jia, Peilin and Zhao, Zhongming and Farias, Monica and Wu, Qi and Milewicz, Dianna M and Sutton, V Reid and Moore, David D and Butte, Nancy F and Krashes, Michael J and Xu, Yong and Chopra, Atul R} } @article {341, title = {Biallelic mutations in IRF8 impair human NK cell maturation and function.}, journal = {J Clin Invest}, volume = {127}, year = {2017}, month = {2017 01 03}, pages = {306-320}, abstract = {

Human NK cell deficiencies are rare yet result in severe and often fatal disease, particularly as a result of viral susceptibility. NK cells develop from hematopoietic stem cells, and few monogenic errors that specifically interrupt NK cell development have been reported. Here we have described biallelic mutations in IRF8, which encodes an interferon regulatory factor, as a cause of familial NK cell deficiency that results in fatal and severe viral disease. Compound heterozygous or homozygous mutations in IRF8 in 3 unrelated families resulted in a paucity of mature CD56dim NK cells and an increase in the frequency of the immature CD56bright NK cells, and this impairment in terminal maturation was also observed in Irf8-/-, but not Irf8+/-, mice. We then determined that impaired maturation was NK cell intrinsic, and gene expression analysis of human NK cell developmental subsets showed that multiple genes were dysregulated by IRF8 mutation. The phenotype was accompanied by deficient NK cell function and was stable over time. Together, these data indicate that human NK cells require IRF8 for development and functional maturation and that dysregulation of this function results in severe human disease, thereby emphasizing a critical role for NK cells in human antiviral defense.

}, keywords = {Alleles, Animals, CD56 Antigen, Female, Gene Expression Regulation, Genetic Predisposition to Disease, Humans, Interferon Regulatory Factors, Killer Cells, Natural, Male, Mice, Mice, Knockout, Mutation, Virus Diseases}, issn = {1558-8238}, doi = {10.1172/JCI86276}, author = {Mace, Emily M and Bigley, Venetia and Gunesch, Justin T and Chinn, Ivan K and Angelo, Laura S and Care, Matthew A and Maisuria, Sheetal and Keller, Michael D and Togi, Sumihito and Watkin, Levi B and LaRosa, David F and Jhangiani, Shalini N and Muzny, Donna M and Stray-Pedersen, Asbj{\o}rg and Coban Akdemir, Zeynep and Smith, Jansen B and Hern{\'a}ndez-Sanabria, Mayra and Le, Duy T and Hogg, Graham D and Cao, Tram N and Freud, Aharon G and Szymanski, Eva P and Savic, Sinisa and Collin, Matthew and Cant, Andrew J and Gibbs, Richard A and Holland, Steven M and Caligiuri, Michael A and Ozato, Keiko and Paust, Silke and Doody, Gina M and Lupski, James R and Orange, Jordan S} } @article {351, title = {Biallelic mutations in the 3{\textquoteright} exonuclease TOE1 cause pontocerebellar hypoplasia and uncover a role in snRNA processing.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Mar}, pages = {457-464}, abstract = {

Deadenylases are best known for degrading the poly(A) tail during mRNA decay. The deadenylase family has expanded throughout evolution and, in mammals, consists of 12 Mg-dependent 3{\textquoteright}-end RNases with substrate specificity that is mostly unknown. Pontocerebellar hypoplasia type 7 (PCH7) is a unique recessive syndrome characterized by neurodegeneration and ambiguous genitalia. We studied 12 human families with PCH7, uncovering biallelic, loss-of-function mutations in TOE1, which encodes an unconventional deadenylase. toe1-morphant zebrafish displayed midbrain and hindbrain degeneration, modeling PCH-like structural defects in vivo. Surprisingly, we found that TOE1 associated with small nuclear RNAs (snRNAs) incompletely processed spliceosomal. These pre-snRNAs contained 3{\textquoteright} genome-encoded tails often followed by post-transcriptionally added adenosines. Human cells with reduced levels of TOE1 accumulated 3{\textquoteright}-end-extended pre-snRNAs, and the immunoisolated TOE1 complex was sufficient for 3{\textquoteright}-end maturation of snRNAs. Our findings identify the cause of a neurodegenerative syndrome linked to snRNA maturation and uncover a key factor involved in the processing of snRNA 3{\textquoteright} ends.

}, keywords = {Alleles, Animals, Cerebellar Diseases, Exonucleases, Female, Humans, Male, Mice, Mutation, Neurodegenerative Diseases, Nuclear Proteins, RNA, Messenger, RNA, Small Nuclear, Spliceosomes, Zebrafish}, issn = {1546-1718}, doi = {10.1038/ng.3762}, author = {Lardelli, Rea M and Schaffer, Ashleigh E and Eggens, Veerle R C and Zaki, Maha S and Grainger, Stephanie and Sathe, Shashank and Van Nostrand, Eric L and Schlachetzki, Zinayida and Rosti, Basak and Akizu, Naiara and Scott, Eric and Silhavy, Jennifer L and Heckman, Laura Dean and Rosti, Rasim Ozgur and Dikoglu, Esra and Gregor, Anne and Guemez-Gamboa, Alicia and Musaev, Damir and Mande, Rohit and Widjaja, Ari and Shaw, Tim L and Markmiller, Sebastian and Marin-Valencia, Isaac and Davies, Justin H and de Meirleir, Linda and Kayserili, H{\"u}lya and Altunoglu, Umut and Freckmann, Mary Louise and Warwick, Linda and Chitayat, David and Blaser, Susan and {\c C}a{\u g}layan, Ahmet Okay and Bilguvar, Kaya and Per, H{\"u}seyin and Fagerberg, Christina and Christesen, Henrik T and Kibaek, Maria and Aldinger, Kimberly A and Manchester, David and Matsumoto, Naomichi and Muramatsu, Kazuhiro and Saitsu, Hirotomo and Shiina, Masaaki and Ogata, Kazuhiro and Foulds, Nicola and Dobyns, William B and Chi, Neil C and Traver, David and Spaccini, Luigina and Bova, Stefania Maria and Gabriel, Stacey B and G{\"u}nel, Murat and Valente, Enza Maria and Nassogne, Marie-Cecile and Bennett, Eric J and Yeo, Gene W and Baas, Frank and Lykke-Andersen, Jens and Gleeson, Joseph G} } @article {537, title = {Disruptions in asymmetric centrosome inheritance and WDR62-Aurora kinase B interactions in primary microcephaly.}, journal = {Sci Rep}, volume = {7}, year = {2017}, month = {2017 03 08}, pages = {43708}, abstract = {

Recessive mutations in WD repeat domain 62 (WDR62) cause microcephaly and a wide spectrum of severe brain malformations. Disruption of the mouse ortholog results in microcephaly underlain by reduced proliferation of neocortical progenitors during late neurogenesis, abnormalities in asymmetric centrosome inheritance leading to neuronal migration delays, and altered neuronal differentiation. Spindle pole localization of WDR62 and mitotic progression are defective in patient-derived fibroblasts, which, similar to mouse neocortical progenitors, transiently arrest at prometaphase. Expression of WDR62 is closely correlated with components of the chromosome passenger complex (CPC), a key regulator of mitosis. Wild type WDR62, but not disease-associated mutant forms, interacts with the CPC core enzyme Aurora kinase B and staining of CPC components at centromeres is altered in patient-derived fibroblasts. Our findings demonstrate critical and diverse functions of WDR62 in neocortical development and provide insight into the mechanisms by which its disruption leads to a plethora of structural abnormalities.

}, keywords = {Animals, Aurora Kinase B, Brain, Cell Cycle, Cell Differentiation, Cell Proliferation, Centrosome, Consanguinity, Disease Models, Animal, Epistasis, Genetic, Fluorescent Antibody Technique, Gene Expression, Humans, Inheritance Patterns, Male, Mice, Mice, Knockout, Microcephaly, Mutation, Nerve Tissue Proteins, Neural Stem Cells, Pedigree, Whole Genome Sequencing}, issn = {2045-2322}, doi = {10.1038/srep43708}, author = {Sgourdou, Paraskevi and Mishra-Gorur, Ketu and Saotome, Ichiko and Henagariu, Octavian and Tuysuz, Beyhan and Campos, Cynthia and Ishigame, Keiko and Giannikou, Krinio and Quon, Jennifer L and {\v S}estan, Nenad and {\c C}a{\u g}layan, Ahmet O and G{\"u}nel, Murat and Louvi, Angeliki} } @article {401, title = {A Dominant Mutation in Nuclear Receptor Interacting Protein 1 Causes Urinary Tract Malformations Dysregulation of Retinoic Acid Signaling.}, journal = {J Am Soc Nephrol}, volume = {28}, year = {2017}, month = {2017 Aug}, pages = {2364-2376}, abstract = {

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of CKD in the first three decades of life. However, for most patients with CAKUT, the causative mutation remains unknown. We identified a kindred with an autosomal dominant form of CAKUT. By whole-exome sequencing, we identified a heterozygous truncating mutation (c.279delG, p.Trp93fs*) of the nuclear receptor interacting protein 1 gene () in all seven affected members. encodes a nuclear receptor transcriptional cofactor that directly interacts with the retinoic acid receptors (RARs) to modulate retinoic acid transcriptional activity. Unlike wild-type NRIP1, the altered NRIP1 protein did not translocate to the nucleus, did not interact with RAR, and failed to inhibit retinoic acid-dependent transcriptional activity upon expression in HEK293 cells. Notably, we also showed that treatment with retinoic acid enhanced NRIP1 binding to RAR RNA hybridization confirmed expression in the developing urogenital system of the mouse. In explant cultures of embryonic kidney rudiments, retinoic acid stimulated expression, whereas a pan-RAR antagonist strongly reduced it. Furthermore, mice heterozygous for a null allele of showed a CAKUT-spectrum phenotype. Finally, expression and knockdown experiments in confirmed an evolutionarily conserved role for in renal development. These data indicate that dominant mutations can cause CAKUT by interference with retinoic acid transcriptional signaling, shedding light on the well documented association between abnormal vitamin A levels and renal malformations in humans, and suggest a possible gene-environment pathomechanism in this disease.

}, keywords = {Adaptor Proteins, Signal Transducing, Animals, Mice, Mutation, Nuclear Proteins, Nuclear Receptor Interacting Protein 1, Signal Transduction, Tretinoin, Urinary Tract}, issn = {1533-3450}, doi = {10.1681/ASN.2016060694}, author = {Vivante, Asaf and Mann, Nina and Yonath, Hagith and Weiss, Anna-Carina and Getwan, Maike and Kaminski, Michael M and Bohnenpoll, Tobias and Teyssier, Catherine and Chen, Jing and Shril, Shirlee and van der Ven, Amelie T and Ityel, Hadas and Schmidt, Johanna Magdalena and Widmeier, Eugen and Bauer, Stuart B and Sanna-Cherchi, Simone and Gharavi, Ali G and Lu, Weining and Magen, Daniella and Shukrun, Rachel and Lifton, Richard P and Tasic, Velibor and Stanescu, Horia C and Cavaill{\`e}s, Vincent and Kleta, Robert and Anikster, Yair and Dekel, Benjamin and Kispert, Andreas and Lienkamp, Soeren S and Hildebrandt, Friedhelm} } @article {423, title = {Exome-wide Association Study Identifies GREB1L Mutations in Congenital Kidney Malformations.}, journal = {Am J Hum Genet}, volume = {101}, year = {2017}, month = {2017 Nov 02}, pages = {789-802}, abstract = {

Renal agenesis and hypodysplasia (RHD) are major causes of pediatric chronic kidney disease and are highly genetically heterogeneous. We conducted whole-exome sequencing in 202 case subjects with RHD and identified diagnostic mutations in genes known to be associated with RHD in 7/202 case subjects. In an additional affected individual with RHD and a congenital heart defect, we found a homozygous loss-of-function (LOF) variant in SLIT3, recapitulating phenotypes reported with Slit3 inactivation in the mouse. To identify genes associated with RHD, we performed an exome-wide association study with 195 unresolved case subjects and 6,905 control subjects. The top signal resided in GREB1L, a gene implicated previously in Hoxb1 and Shha signaling in zebrafish. The significance of the association, which was p = 2.0~{\texttimes} 10 for novel LOF, increased to p = 4.1~{\texttimes} 10 for LOF and deleterious missense variants combined, and augmented further after accounting for segregation and de novo inheritance of rare variants (joint p = 2.3~{\texttimes} 10). Finally, CRISPR/Cas9 disruption or knockdown of greb1l in zebrafish caused specific pronephric defects, which were rescued by wild-type human GREB1L mRNA, but not mRNA containing alleles identified in case subjects. Together, our study provides insight into the genetic landscape of kidney malformations in humans, presents multiple candidates, and identifies SLIT3 and GREB1L as genes implicated in the pathogenesis of RHD.

}, keywords = {Alleles, Animals, Case-Control Studies, Clustered Regularly Interspaced Short Palindromic Repeats, Congenital Abnormalities, Exome, Female, Genetic Heterogeneity, Genome-Wide Association Study, Genotype, Heredity, Homozygote, Humans, Kidney, Kidney Diseases, Male, Membrane Proteins, Mice, Mutation, Neoplasm Proteins, Phenotype, RNA, Long Noncoding, Urinary Tract, Urogenital Abnormalities, Zebrafish}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.09.018}, author = {Sanna-Cherchi, Simone and Khan, Kamal and Westland, Rik and Krithivasan, Priya and Fievet, Lorraine and Rasouly, Hila Milo and Ionita-Laza, Iuliana and Capone, Valentina P and Fasel, David A and Kiryluk, Krzysztof and Kamalakaran, Sitharthan and Bodria, Monica and Otto, Edgar A and Sampson, Matthew G and Gillies, Christopher E and Vega-Warner, Virginia and Vukojevic, Katarina and Pediaditakis, Igor and Makar, Gabriel S and Mitrotti, Adele and Verbitsky, Miguel and Martino, Jeremiah and Liu, Qingxue and Na, Young-Ji and Goj, Vinicio and Ardissino, Gianluigi and Gigante, Maddalena and Gesualdo, Loreto and Janezcko, Magdalena and Zaniew, Marcin and Mendelsohn, Cathy Lee and Shril, Shirlee and Hildebrandt, Friedhelm and van Wijk, Joanna A E and Arapovic, Adela and Saraga, Marijan and Allegri, Landino and Izzi, Claudia and Scolari, Francesco and Tasic, Velibor and Ghiggeri, Gian Marco and Latos-Bielenska, Anna and Materna-Kiryluk, Anna and Mane, Shrikant and Goldstein, David B and Lifton, Richard P and Katsanis, Nicholas and Davis, Erica E and Gharavi, Ali G} } @article {350, title = {Genetic Drivers of Kidney Defects in the DiGeorge Syndrome.}, journal = {N Engl J Med}, volume = {376}, year = {2017}, month = {2017 02 23}, pages = {742-754}, abstract = {

BACKGROUND: The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown.

METHODS: We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice.

RESULTS: We identified heterozygous deletions of 22q11.2 in 1.1\% of the patients with congenital kidney anomalies and in 0.01\% of population controls (odds ratio, 81.5; P=4.5{\texttimes}10). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies.

CONCLUSIONS: We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. (Funded by the National Institutes of Health and others.).

}, keywords = {Adaptor Proteins, Signal Transducing, Adolescent, Animals, Child, Chromosome Deletion, Chromosomes, Human, Pair 22, DiGeorge Syndrome, Exome, Female, Haploinsufficiency, Heterozygote, Humans, Infant, Infant, Newborn, Kidney, Male, Mice, Models, Animal, Nuclear Proteins, Sequence Analysis, DNA, Urinary Tract, Young Adult, Zebrafish}, issn = {1533-4406}, doi = {10.1056/NEJMoa1609009}, author = {Lopez-Rivera, Esther and Liu, Yangfan P and Verbitsky, Miguel and Anderson, Blair R and Capone, Valentina P and Otto, Edgar A and Yan, Zhonghai and Mitrotti, Adele and Martino, Jeremiah and Steers, Nicholas J and Fasel, David A and Vukojevic, Katarina and Deng, Rong and Racedo, Silvia E and Liu, Qingxue and Werth, Max and Westland, Rik and Vivante, Asaf and Makar, Gabriel S and Bodria, Monica and Sampson, Matthew G and Gillies, Christopher E and Vega-Warner, Virginia and Maiorana, Mariarosa and Petrey, Donald S and Honig, Barry and Lozanovski, Vladimir J and Salomon, R{\'e}mi and Heidet, Laurence and Carpentier, Wassila and Gaillard, Dominique and Carrea, Alba and Gesualdo, Loreto and Cusi, Daniele and Izzi, Claudia and Scolari, Francesco and van Wijk, Joanna A E and Arapovic, Adela and Saraga-Babic, Mirna and Saraga, Marijan and Kunac, Nenad and Samii, Ali and McDonald-McGinn, Donna M and Crowley, Terrence B and Zackai, Elaine H and Drozdz, Dorota and Miklaszewska, Monika and Tkaczyk, Marcin and Sikora, Przemyslaw and Szczepanska, Maria and Mizerska-Wasiak, Malgorzata and Krzemien, Grazyna and Szmigielska, Agnieszka and Zaniew, Marcin and Darlow, John M and Puri, Prem and Barton, David and Casolari, Emilio and Furth, Susan L and Warady, Bradley A and Gucev, Zoran and Hakonarson, Hakon and Flogelova, Hana and Tasic, Velibor and Latos-Bielenska, Anna and Materna-Kiryluk, Anna and Allegri, Landino and Wong, Craig S and Drummond, Iain A and D{\textquoteright}Agati, Vivette and Imamoto, Akira and Barasch, Jonathan M and Hildebrandt, Friedhelm and Kiryluk, Krzysztof and Lifton, Richard P and Morrow, Bernice E and Jeanpierre, Cecile and Papaioannou, Virginia E and Ghiggeri, Gian Marco and Gharavi, Ali G and Katsanis, Nicholas and Sanna-Cherchi, Simone} } @article {358, title = {Germline mutations in ABL1 cause an autosomal dominant syndrome characterized by congenital heart defects and skeletal malformations.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Apr}, pages = {613-617}, abstract = {

ABL1 is a proto-oncogene well known as part of the fusion gene BCR-ABL1 in the Philadelphia chromosome of leukemia cancer cells. Inherited germline ABL1 changes have not been associated with genetic disorders. Here we report ABL1 germline variants cosegregating with an autosomal dominant disorder characterized by congenital heart disease, skeletal abnormalities, and failure to thrive. The variant c.734A>G (p.Tyr245Cys) was found to occur de novo or cosegregate with disease in five individuals (families 1-3). Additionally, a de novo c.1066G>A (p.Ala356Thr) variant was identified in a sixth individual (family 4). We overexpressed the mutant constructs in HEK 293T cells and observed increased tyrosine phosphorylation, suggesting increased ABL1 kinase activities associated with both the p.Tyr245Cys and p.Ala356Thr substitutions. Our clinical and experimental findings, together with previously reported teratogenic effects of selective BCR-ABL inhibitors in humans and developmental defects in Abl1 knockout mice, suggest that ABL1 has an important role during organismal development.

}, keywords = {Abnormalities, Multiple, Animals, Bone Diseases, Developmental, Cell Line, Chromosome Disorders, Craniofacial Abnormalities, Feeding and Eating Disorders, Female, Fusion Proteins, bcr-abl, Germ-Line Mutation, Heart Defects, Congenital, HEK293 Cells, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Limb Deformities, Congenital, Male, Mice, Mice, Knockout, Philadelphia Chromosome, Phosphorylation, Signal Transduction}, issn = {1546-1718}, doi = {10.1038/ng.3815}, author = {Wang, Xia and Charng, Wu-Lin and Chen, Chun-An and Rosenfeld, Jill A and Al Shamsi, Aisha and Al-Gazali, Lihadh and McGuire, Marianne and Mew, Nicholas Ah and Arnold, Georgianne L and Qu, Chunjing and Ding, Yan and Muzny, Donna M and Gibbs, Richard A and Eng, Christine M and Walkiewicz, Magdalena and Xia, Fan and Plon, Sharon E and Lupski, James R and Schaaf, Christian P and Yang, Yaping} } @article {402, title = {Isolated polycystic liver disease genes define effectors of polycystin-1 function.}, journal = {J Clin Invest}, volume = {127}, year = {2017}, month = {2017 May 01}, pages = {1772-1785}, abstract = {

Dominantly inherited isolated polycystic liver disease (PCLD) consists of liver cysts that are radiologically and pathologically identical to those seen in autosomal dominant polycystic kidney disease, but without clinically relevant kidney cysts. The causative genes are known for fewer than 40\% of PCLD index cases. Here, we have used whole exome sequencing in a discovery cohort of 102 unrelated patients who were excluded for mutations in the 2 most common PCLD genes, PRKCSH and SEC63, to identify heterozygous loss-of-function mutations in 3 additional genes, ALG8, GANAB, and SEC61B. Similarly to PRKCSH and SEC63, these genes encode proteins that are integral to the protein biogenesis pathway in the endoplasmic reticulum. We inactivated these candidate genes in cell line models to show that loss of function of each results in defective maturation and trafficking of polycystin-1, the central determinant of cyst pathogenesis. Despite acting in a common pathway, each PCLD gene product demonstrated distinct effects on polycystin-1 biogenesis. We also found enrichment on a genome-wide basis of heterozygous mutations in the autosomal recessive polycystic kidney disease gene PKHD1, indicating that adult PKHD1 carriers can present with clinical PCLD. These findings define genetic and biochemical modulators of polycystin-1 function and provide a more complete definition of the spectrum of dominant human polycystic diseases.

}, keywords = {Adult, Animals, Cell Line, Transformed, Cysts, Endoplasmic Reticulum, Female, Genome-Wide Association Study, Glucosidases, Glucosyltransferases, Heterozygote, Humans, Intracellular Signaling Peptides and Proteins, Liver Diseases, Male, Membrane Proteins, Mice, Mutation, SEC Translocation Channels, TRPP Cation Channels}, issn = {1558-8238}, doi = {10.1172/JCI90129}, author = {Besse, Whitney and Dong, Ke and Choi, Jungmin and Punia, Sohan and Fedeles, Sorin V and Choi, Murim and Gallagher, Anna-Rachel and Huang, Emily B and Gulati, Ashima and Knight, James and Mane, Shrikant and Tahvanainen, Esa and Tahvanainen, Pia and Sanna-Cherchi, Simone and Lifton, Richard P and Watnick, Terry and Pei, York P and Torres, Vicente E and Somlo, Stefan} } @article {634, title = {Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Oct}, pages = {1529-1538}, abstract = {

Galloway-Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms.

}, keywords = {Animals, Apoptosis, Carrier Proteins, Cell Movement, CRISPR-Cas Systems, Cytoskeleton, DNA Repair, Endoplasmic Reticulum Stress, Gene Knockout Techniques, Hernia, Hiatal, Humans, Intracellular Signaling Peptides and Proteins, Metalloendopeptidases, Mice, Microcephaly, Models, Molecular, Multiprotein Complexes, Mutation, Nephrosis, Nephrotic Syndrome, Podocytes, Protein Conformation, Protein-Serine-Threonine Kinases, RNA Processing, Post-Transcriptional, RNA, Transfer, Telomere Homeostasis, Zebrafish, Zebrafish Proteins}, issn = {1546-1718}, doi = {10.1038/ng.3933}, author = {Braun, Daniela A and Rao, Jia and Mollet, Geraldine and Schapiro, David and Daugeron, Marie-Claire and Tan, Weizhen and Gribouval, Olivier and Boyer, Olivia and Revy, Patrick and Jobst-Schwan, Tilman and Schmidt, Johanna Magdalena and Lawson, Jennifer A and Schanze, Denny and Ashraf, Shazia and Ullmann, Jeremy F P and Hoogstraten, Charlotte A and Boddaert, Nathalie and Collinet, Bruno and Martin, Ga{\"e}lle and Liger, Dominique and Lovric, Svjetlana and Furlano, Monica and Guerrera, I Chiara and Sanchez-Ferras, Oraly and Hu, Jennifer F and Boschat, Anne-Claire and Sanquer, Sylvia and Menten, Bj{\"o}rn and Vergult, Sarah and De Rocker, Nina and Airik, Merlin and Hermle, Tobias and Shril, Shirlee and Widmeier, Eugen and Gee, Heon Yung and Choi, Won-Il and Sadowski, Carolin E and Pabst, Werner L and Warejko, Jillian K and Daga, Ankana and Basta, Tamara and Matejas, Verena and Scharmann, Karin and Kienast, Sandra D and Behnam, Babak and Beeson, Brendan and Begtrup, Amber and Bruce, Malcolm and Ch{\textquoteright}ng, Gaik-Siew and Lin, Shuan-Pei and Chang, Jui-Hsing and Chen, Chao-Huei and Cho, Megan T and Gaffney, Patrick M and Gipson, Patrick E and Hsu, Chyong-Hsin and Kari, Jameela A and Ke, Yu-Yuan and Kiraly-Borri, Cathy and Lai, Wai-Ming and Lemyre, Emmanuelle and Littlejohn, Rebecca Okashah and Masri, Amira and Moghtaderi, Mastaneh and Nakamura, Kazuyuki and Ozaltin, Fatih and Praet, Marleen and Prasad, Chitra and Prytula, Agnieszka and Roeder, Elizabeth R and Rump, Patrick and Schnur, Rhonda E and Shiihara, Takashi and Sinha, Manish D and Soliman, Neveen A and Soulami, Kenza and Sweetser, David A and Tsai, Wen-Hui and Tsai, Jeng-Daw and Topaloglu, Rezan and Vester, Udo and Viskochil, David H and Vatanavicharn, Nithiwat and Waxler, Jessica L and Wierenga, Klaas J and Wolf, Matthias T F and Wong, Sik-Nin and Leidel, Sebastian A and Truglio, Gessica and Dedon, Peter C and Poduri, Annapurna and Mane, Shrikant and Lifton, Richard P and Bouchard, Maxime and Kannu, Peter and Chitayat, David and Magen, Daniella and Callewaert, Bert and van Tilbeurgh, Herman and Zenker, Martin and Antignac, Corinne and Hildebrandt, Friedhelm} } @article {405, title = {Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency.}, journal = {J Clin Invest}, volume = {127}, year = {2017}, month = {2017 Mar 01}, pages = {912-928}, abstract = {

Steroid-resistant nephrotic syndrome (SRNS) causes 15\% of chronic kidney disease cases. A mutation in 1 of over 40 monogenic genes can be detected in approximately 30\% of individuals with SRNS whose symptoms manifest before 25 years of age. However, in many patients, the genetic etiology remains unknown. Here, we have performed whole exome sequencing to identify recessive causes of SRNS. In 7 families with SRNS and facultative ichthyosis, adrenal insufficiency, immunodeficiency, and neurological defects, we identified 9 different recessive mutations in SGPL1, which encodes sphingosine-1-phosphate (S1P) lyase. All mutations resulted in reduced or absent SGPL1 protein and/or enzyme activity. Overexpression of cDNA representing SGPL1 mutations resulted in subcellular mislocalization of SGPL1. Furthermore, expression of WT human SGPL1 rescued growth of SGPL1-deficient dpl1Δ yeast strains, whereas expression of disease-associated variants did not. Immunofluorescence revealed SGPL1 expression in mouse podocytes and mesangial cells. Knockdown of Sgpl1 in rat mesangial cells inhibited cell migration, which was partially rescued by VPC23109, an S1P receptor antagonist. In Drosophila, Sply mutants, which lack SGPL1, displayed a phenotype reminiscent of nephrotic syndrome in nephrocytes. WT Sply, but not the disease-associated variants, rescued this phenotype. Together, these results indicate that SGPL1 mutations cause a syndromic form of SRNS.

}, keywords = {Aldehyde-Lyases, Animals, Cell Line, Cell Movement, Drosophila melanogaster, Drosophila Proteins, Female, Humans, Ichthyosis, Lamellar, Male, Mesangial Cells, Mice, Mice, Knockout, Mutation, Nephrotic Syndrome, Protein Transport, Rats}, issn = {1558-8238}, doi = {10.1172/JCI89626}, author = {Lovric, Svjetlana and Goncalves, Sara and Gee, Heon Yung and Oskouian, Babak and Srinivas, Honnappa and Choi, Won-Il and Shril, Shirlee and Ashraf, Shazia and Tan, Weizhen and Rao, Jia and Airik, Merlin and Schapiro, David and Braun, Daniela A and Sadowski, Carolin E and Widmeier, Eugen and Jobst-Schwan, Tilman and Schmidt, Johanna Magdalena and Girik, Vladimir and Capitani, Guido and Suh, Jung H and Lachauss{\'e}e, No{\"e}lle and Arrondel, Christelle and Patat, Julie and Gribouval, Olivier and Furlano, Monica and Boyer, Olivia and Schmitt, Alain and Vuiblet, Vincent and Hashmi, Seema and Wilcken, Rainer and Bernier, Francois P and Innes, A Micheil and Parboosingh, Jillian S and Lamont, Ryan E and Midgley, Julian P and Wright, Nicola and Majewski, Jacek and Zenker, Martin and Schaefer, Franz and Kuss, Navina and Greil, Johann and Giese, Thomas and Schwarz, Klaus and Catheline, Vilain and Schanze, Denny and Franke, Ingolf and Sznajer, Yves and Truant, Anne S and Adams, Brigitte and D{\'e}sir, Julie and Biemann, Ronald and Pei, York and Ars, Elisabet and Lloberas, Nuria and Madrid, Alvaro and Dharnidharka, Vikas R and Connolly, Anne M and Willing, Marcia C and Cooper, Megan A and Lifton, Richard P and Simons, Matias and Riezman, Howard and Antignac, Corinne and Saba, Julie D and Hildebrandt, Friedhelm} } @article {454, title = {P4HA1 mutations cause a unique congenital disorder of connective tissue involving tendon, bone, muscle and the eye.}, journal = {Hum Mol Genet}, volume = {26}, year = {2017}, month = {2017 06 15}, pages = {2207-2217}, abstract = {

Collagen prolyl 4-hydroxylases (C-P4Hs) play a central role in the formation and stabilization of the triple helical domain of collagens. P4HA1 encodes the catalytic α(I) subunit of the main C-P4H isoenzyme (C-P4H-I). We now report human bi-allelic P4HA1 mutations in a family with a congenital-onset disorder of connective tissue, manifesting as early-onset joint hypermobility, joint contractures, muscle weakness and bone dysplasia as well as high myopia, with evidence of clinical improvement of motor function over time in the surviving patient. Similar to P4ha1 null mice, which die prenatally, the muscle tissue from P1 and P2 was found to have reduced collagen IV immunoreactivity at the muscle basement membrane. Patients were compound heterozygous for frameshift and splice site mutations leading to reduced, but not absent, P4HA1 protein level and C-P4H activity in dermal fibroblasts compared to age-matched control samples. Differential scanning calorimetry revealed reduced thermal stability of collagen in patient-derived dermal fibroblasts versus age-matched control samples. Mutations affecting the family of C-P4Hs, and in particular C-P4H-I, should be considered in patients presenting with congenital connective tissue/myopathy overlap disorders with joint hypermobility, contractures, mild skeletal dysplasia and high myopia.

}, keywords = {Animals, Basement Membrane, Bone and Bones, Child, Collagen Type IV, Connective Tissue, Humans, Male, Mice, Mice, Knockout, Muscles, Mutation, Osteochondrodysplasias, Procollagen-Proline Dioxygenase, Prolyl Hydroxylases, Tendons}, issn = {1460-2083}, doi = {10.1093/hmg/ddx110}, author = {Zou, Yaqun and Donkervoort, Sandra and Salo, Antti M and Foley, A Reghan and Barnes, Aileen M and Hu, Ying and Makareeva, Elena and Leach, Meganne E and Mohassel, Payam and Dastgir, Jahannaz and Deardorff, Matthew A and Cohn, Ronald D and DiNonno, Wendy O and Malfait, Fransiska and Lek, Monkol and Leikin, Sergey and Marini, Joan C and Myllyharju, Johanna and B{\"o}nnemann, Carsten G} } @article {66, title = {Asprosin, a Fasting-Induced Glucogenic Protein Hormone.}, journal = {Cell}, volume = {165}, year = {2016}, month = {2016 Apr 21}, pages = {566-79}, abstract = {

Hepatic glucose release into the circulation is vital for brain function and survival during periods of fasting and is modulated by an array of hormones that precisely regulate plasma glucose levels. We have identified a fasting-induced protein hormone that modulates hepatic glucose release. It is the C-terminal cleavage product of profibrillin, and we name it Asprosin. Asprosin is secreted by white adipose, circulates at nanomolar levels, and is recruited to the liver, where it activates the G protein-cAMP-PKA pathway, resulting in rapid glucose release into the circulation. Humans and mice with insulin resistance show pathologically elevated plasma asprosin, and its loss of function via immunologic or genetic means~has a profound glucose- and insulin-lowering effect secondary to reduced hepatic glucose release. Asprosin represents a glucogenic protein hormone, and therapeutically targeting it may be beneficial in type II diabetes and metabolic syndrome.

}, keywords = {Adipose Tissue, White, Amino Acid Sequence, Animals, Antibodies, Circadian Rhythm, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Fasting, Female, Fetal Growth Retardation, Glucose, Humans, Insulin, Liver, Male, Mice, Mice, Inbred C57BL, Mice, Obese, Microfilament Proteins, Molecular Sequence Data, Peptide Fragments, Peptide Hormones, Progeria, Recombinant Proteins, Sequence Alignment}, issn = {1097-4172}, doi = {10.1016/j.cell.2016.02.063}, author = {Romere, Chase and Duerrschmid, Clemens and Bournat, Juan and Constable, Petra and Jain, Mahim and Xia, Fan and Saha, Pradip K and Del Solar, Maria and Zhu, Bokai and York, Brian and Sarkar, Poonam and Rendon, David A and Gaber, M Waleed and LeMaire, Scott A and Coselli, Joseph S and Milewicz, Dianna M and Sutton, V Reid and Butte, Nancy F and Moore, David D and Chopra, Atul R} } @article {24, title = {Bi-allelic Mutations in PKD1L1 Are Associated with Laterality Defects in Humans.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Oct 06}, pages = {886-893}, abstract = {

Disruption of the establishment of left-right (L-R) asymmetry leads to situs anomalies ranging from situs inversus totalis (SIT) to situs ambiguus (heterotaxy). The genetic causes of laterality defects in humans are highly heterogeneous. Via whole-exome sequencing (WES), we identified homozygous mutations in PKD1L1 from three affected individuals in two unrelated families. PKD1L1 encodes a polycystin-1-like protein and its loss of function is known to cause laterality defects in mouse and medaka fish models. Family 1 had one fetus and one deceased child with heterotaxy and complex congenital heart malformations. WES identified a homozygous splicing mutation, c.6473+2_6473+3delTG, which disrupts the invariant splice donor site in intron 42, in both affected individuals. In the second family, a homozygous c.5072G>C (p.Cys1691Ser) missense mutation was detected in an individual with SIT and congenital heart disease. The p.Cys1691Ser substitution affects a highly conserved cysteine residue and is predicted by molecular modeling to disrupt a disulfide bridge essential for the proper folding of the G protein-coupled receptor proteolytic site (GPS) motif. Damaging effects associated with substitutions of this conserved cysteine residue in the GPS motif have also been reported in other genes, namely GPR56, BAI3, and PKD1 in human and lat-1 in C.~elegans, further supporting the likely pathogenicity of p.Cys1691Ser in PKD1L1. The identification of bi-allelic PKD1L1 mutations recapitulates previous findings regarding phenotypic consequences of loss of function of the orthologous genes in mice and medaka fish and further expands our understanding of genetic contributions to laterality defects in humans.

}, keywords = {Alleles, Amino Acid Motifs, Amino Acid Sequence, Animals, Caenorhabditis elegans, Cysteine, Exome, Female, Fetal Diseases, Functional Laterality, Heart Defects, Congenital, Heterotaxy Syndrome, Homozygote, Humans, Infant, Newborn, Introns, Male, Membrane Proteins, Mice, Middle Aged, Models, Molecular, Mutation, Mutation, Missense, Oryzias, Pedigree, RNA Splicing, Situs Inversus}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.07.011}, author = {Vetrini, Francesco and D{\textquoteright}Alessandro, Lisa C A and Akdemir, Zeynep C and Braxton, Alicia and Azamian, Mahshid S and Eldomery, Mohammad K and Miller, Kathryn and Kois, Chelsea and Sack, Virginia and Shur, Natasha and Rijhsinghani, Asha and Chandarana, Jignesh and Ding, Yan and Holtzman, Judy and Jhangiani, Shalini N and Muzny, Donna M and Gibbs, Richard A and Eng, Christine M and Hanchard, Neil A and Harel, Tamar and Rosenfeld, Jill A and Belmont, John W and Lupski, James R and Yang, Yaping} } @article {60, title = {The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery.}, journal = {Nat Genet}, volume = {48}, year = {2016}, month = {2016 06}, pages = {648-56}, abstract = {

Cilia use microtubule-based intraflagellar transport (IFT) to organize intercellular signaling. Ciliopathies are a spectrum of human diseases resulting from defects in cilia structure or function. The mechanisms regulating the assembly of ciliary multiprotein complexes and the transport of these complexes to the base of cilia remain largely unknown. Combining proteomics, in vivo imaging and genetic analysis of proteins linked to planar cell polarity (Inturned, Fuzzy and Wdpcp), we identified and characterized a new genetic module, which we term CPLANE (ciliogenesis and planar polarity effector), and an extensive associated protein network. CPLANE proteins physically and functionally interact with the poorly understood ciliopathy-associated protein Jbts17 at basal bodies, where they act to recruit a specific subset of IFT-A proteins. In the absence of CPLANE, defective IFT-A particles enter the axoneme and IFT-B trafficking is severely perturbed. Accordingly, mutation of CPLANE genes elicits specific ciliopathy phenotypes in mouse models and is associated with ciliopathies in human patients.

}, keywords = {Animals, Ciliopathies, Flagella, Humans, Mice, Mutation, Phenotype, Protein Binding, Protein Transport, Proteins}, issn = {1546-1718}, doi = {10.1038/ng.3558}, author = {Toriyama, Michinori and Lee, Chanjae and Taylor, S Paige and Duran, Ivan and Cohn, Daniel H and Bruel, Ange-Line and Tabler, Jacqueline M and Drew, Kevin and Kelly, Marcus R and Kim, Sukyoung and Park, Tae Joo and Braun, Daniela A and Pierquin, Ghislaine and Biver, Armand and Wagner, Kerstin and Malfroot, Anne and Panigrahi, Inusha and Franco, Brunella and Al-Lami, Hadeel Adel and Yeung, Yvonne and Choi, Yeon Ja and Duffourd, Yannis and Faivre, Laurence and Rivi{\`e}re, Jean-Baptiste and Chen, Jiang and Liu, Karen J and Marcotte, Edward M and Hildebrandt, Friedhelm and Thauvin-Robinet, Christel and Krakow, Deborah and Jackson, Peter K and Wallingford, John B} } @article {69, title = {De Novo and Rare Variants at Multiple Loci Support the Oligogenic Origins of Atrioventricular Septal Heart Defects.}, journal = {PLoS Genet}, volume = {12}, year = {2016}, month = {2016 Apr}, pages = {e1005963}, abstract = {

Congenital heart disease (CHD) has a complex genetic etiology, and recent studies suggest that high penetrance de novo mutations may account for only a small fraction of disease. In a multi-institutional cohort surveyed by exome sequencing, combining analysis of 987 individuals (discovery cohort of 59 affected trios and 59 control trios, and a replication cohort of 100 affected singletons and 533 unaffected singletons) we observe variation at novel and known loci related to a specific cardiac malformation the atrioventricular septal defect (AVSD). In a primary analysis, by combining developmental coexpression networks with inheritance modeling, we identify a de novo mutation in the DNA binding domain of NR1D2 (p.R175W). We show that p.R175W changes the transcriptional activity of Nr1d2 using an in vitro transactivation model in HUVEC cells. Finally, we demonstrate previously unrecognized cardiovascular malformations in the Nr1d2tm1-Dgen knockout mouse. In secondary analyses we map genetic variation to protein-interaction networks suggesting a role for two collagen genes in AVSD, which we corroborate by burden testing in a second replication cohort of 100 AVSDs and 533 controls (p = 8.37e-08). Finally, we apply a rare-disease inheritance model to identify variation in genes previously associated with CHD (ZFPM2, NSD1, NOTCH1, VCAN, and MYH6), cardiac malformations in mouse models (ADAM17, CHRD, IFT140, PTPRJ, RYR1 and ATE1), and hypomorphic alleles of genes causing syndromic CHD (EHMT1, SRCAP, BBS2, NOTCH2, and KMT2D) in 14 of 59 trios, greatly exceeding variation in control trios without CHD (p = 9.60e-06). In total, 32\% of trios carried at least one putatively disease-associated variant across 19 loci,suggesting that inherited and de novo variation across a heterogeneous group of loci may contribute to disease risk.

}, keywords = {Animals, Female, Heart Septal Defects, Heterozygote, Homozygote, Humans, Male, Mice, Mice, Knockout, Mutation, Pedigree}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1005963}, author = {Priest, James R and Osoegawa, Kazutoyo and Mohammed, Nebil and Nanda, Vivek and Kundu, Ramendra and Schultz, Kathleen and Lammer, Edward J and Girirajan, Santhosh and Scheetz, Todd and Waggott, Daryl and Haddad, Francois and Reddy, Sushma and Bernstein, Daniel and Burns, Trudy and Steimle, Jeffrey D and Yang, Xinan H and Moskowitz, Ivan P and Hurles, Matthew and Lifton, Richard P and Nickerson, Debbie and Bamshad, Michael and Eichler, Evan E and Mital, Seema and Sheffield, Val and Quertermous, Thomas and Gelb, Bruce D and Portman, Michael and Ashley, Euan A} } @article {80, title = {FAT1 mutations cause a glomerulotubular nephropathy.}, journal = {Nat Commun}, volume = {7}, year = {2016}, month = {2016 Feb 24}, pages = {10822}, abstract = {

Steroid-resistant nephrotic syndrome (SRNS) causes 15\% of chronic kidney disease (CKD). Here we show that recessive mutations in FAT1 cause a distinct renal disease entity in four families with a combination of SRNS, tubular ectasia, haematuria and facultative neurological involvement. Loss of FAT1 results in decreased cell adhesion and migration in fibroblasts and podocytes and the decreased migration is partially reversed by a RAC1/CDC42 activator. Podocyte-specific deletion of Fat1 in mice induces abnormal glomerular filtration barrier development, leading to podocyte foot process effacement. Knockdown of Fat1 in renal tubular cells reduces migration, decreases active RAC1 and CDC42, and induces defects in lumen formation. Knockdown of fat1 in zebrafish causes pronephric cysts, which is partially rescued by RAC1/CDC42 activators, confirming a role of the two small GTPases in the pathogenesis. These findings provide new insights into the pathogenesis of SRNS and tubulopathy, linking FAT1 and RAC1/CDC42 to podocyte and tubular cell function.

}, keywords = {Animals, Cadherins, cdc42 GTP-Binding Protein, Cell Adhesion, Cell Movement, Dilatation, Pathologic, Fibroblasts, Gene Knockdown Techniques, Hematuria, Humans, Kidney Tubules, Lissencephaly, Mice, Mutation, Nephrotic Syndrome, Podocytes, rac1 GTP-Binding Protein, Syndrome, Zebrafish, Zebrafish Proteins}, issn = {2041-1723}, doi = {10.1038/ncomms10822}, author = {Gee, Heon Yung and Sadowski, Carolin E and Aggarwal, Pardeep K and Porath, Jonathan D and Yakulov, Toma A and Schueler, Markus and Lovric, Svjetlana and Ashraf, Shazia and Braun, Daniela A and Halbritter, Jan and Fang, Humphrey and Airik, Rannar and Vega-Warner, Virginia and Cho, Kyeong Jee and Chan, Timothy A and Morris, Luc G T and ffrench-Constant, Charles and Allen, Nicholas and McNeill, Helen and B{\"u}scher, Rainer and Kyrieleis, Henriette and Wallot, Michael and Gaspert, Ariana and Kistler, Thomas and Milford, David V and Saleem, Moin A and Keng, Wee Teik and Alexander, Stephen I and Valentini, Rudolph P and Licht, Christoph and Teh, Jun C and Bogdanovic, Radovan and Koziell, Ania and Bierzynska, Agnieszka and Soliman, Neveen A and Otto, Edgar A and Lifton, Richard P and Holzman, Lawrence B and Sibinga, Nicholas E S and Walz, Gerd and Tufro, Alda and Hildebrandt, Friedhelm} } @article {9, title = {Identification of a RAI1-associated disease network through integration of exome sequencing, transcriptomics, and 3D genomics.}, journal = {Genome Med}, volume = {8}, year = {2016}, month = {2016 Nov 01}, pages = {105}, abstract = {

BACKGROUND: Smith-Magenis syndrome (SMS) is a developmental disability/multiple congenital anomaly disorder resulting from haploinsufficiency of RAI1. It is characterized by distinctive facial features, brachydactyly, sleep disturbances, and stereotypic behaviors.

METHODS: We investigated a cohort of 15 individuals with a clinical suspicion of SMS who showed neither deletion in the SMS critical region nor damaging variants in RAI1 using whole exome sequencing. A combination of network analysis (co-expression and biomedical text mining), transcriptomics, and circularized chromatin conformation capture (4C-seq) was applied to verify whether modified genes are part of the same disease network as known SMS-causing genes.

RESULTS: Potentially deleterious variants were identified in nine of these individuals using whole-exome sequencing. Eight of these changes affect KMT2D, ZEB2, MAP2K2, GLDC, CASK, MECP2, KDM5C, and POGZ, known to be associated with Kabuki syndrome 1, Mowat-Wilson syndrome, cardiofaciocutaneous syndrome, glycine encephalopathy, mental retardation and microcephaly with pontine and cerebellar hypoplasia, X-linked mental retardation 13, X-linked mental retardation Claes-Jensen type, and White-Sutton syndrome, respectively. The ninth individual carries a de novo variant in JAKMIP1, a regulator of neuronal translation that was recently found deleted in a patient with autism spectrum disorder. Analyses of co-expression and biomedical text mining suggest that these pathologies and SMS are part of the same disease network. Further support for this hypothesis was obtained from transcriptome profiling that showed that the expression levels of both Zeb2 and Map2k2 are perturbed in Rai1 mice. As an orthogonal approach to potentially contributory disease gene variants, we used chromatin conformation capture to reveal chromatin contacts between RAI1 and the loci flanking ZEB2 and GLDC, as well as between RAI1 and human orthologs of the genes that show perturbed expression in our Rai1 mouse model.

CONCLUSIONS: These holistic studies of RAI1 and its interactions allow insights into SMS and other disorders associated with intellectual disability and behavioral abnormalities. Our findings support a pan-genomic approach to the molecular diagnosis of a distinctive disorder.

}, keywords = {Animals, Embryo, Mammalian, Exome, Female, Gene Regulatory Networks, Genomics, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutation, Phenotype, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger, Smith-Magenis Syndrome, Trans-Activators, Transcription Factors, Transcriptome}, issn = {1756-994X}, doi = {10.1186/s13073-016-0359-z}, author = {Loviglio, Maria Nicla and Beck, Christine R and White, Janson J and Leleu, Marion and Harel, Tamar and Guex, Nicolas and Niknejad, Anne and Bi, Weimin and Chen, Edward S and Crespo, Isaac and Yan, Jiong and Charng, Wu-Lin and Gu, Shen and Fang, Ping and Coban-Akdemir, Zeynep and Shaw, Chad A and Jhangiani, Shalini N and Muzny, Donna M and Gibbs, Richard A and Rougemont, Jacques and Xenarios, Ioannis and Lupski, James R and Reymond, Alexandre} } @article {410, title = {Impaired Amino Acid Transport at the Blood Brain Barrier Is a Cause of Autism Spectrum Disorder.}, journal = {Cell}, volume = {167}, year = {2016}, month = {2016 Dec 01}, pages = {1481-1494.e18}, abstract = {

Autism spectrum disorders (ASD) are a group of genetic disorders often overlapping with other neurological conditions. We previously described abnormalities in the branched-chain amino acid (BCAA) catabolic pathway as a cause of ASD. Here, we show that the solute carrier transporter 7a5 (SLC7A5), a large neutral amino acid transporter localized at the blood brain barrier (BBB), has an essential role in maintaining normal levels of brain BCAAs. In mice, deletion of Slc7a5 from the endothelial cells of the BBB leads to atypical brain amino acid profile, abnormal mRNA translation, and severe neurological abnormalities. Furthermore, we identified several patients with autistic traits and motor delay carrying deleterious homozygous mutations in the SLC7A5 gene. Finally, we demonstrate that BCAA intracerebroventricular administration ameliorates abnormal behaviors in adult mutant mice. Our data elucidate a neurological syndrome defined by SLC7A5 mutations and support an essential role for the BCAA in human brain function.

}, keywords = {Amino Acids, Animals, Autism Spectrum Disorder, Blood-Brain Barrier, Brain, Female, Humans, Infant, Infant, Newborn, Large Neutral Amino Acid-Transporter 1, Male, Mice, Mice, Knockout, Mutation, Pedigree, Protein Biosynthesis, Receptor, TIE-2}, issn = {1097-4172}, doi = {10.1016/j.cell.2016.11.013}, author = {T{\u a}rlungeanu, Dora C and Deliu, Elena and Dotter, Christoph P and Kara, Majdi and Janiesch, Philipp Christoph and Scalise, Mariafrancesca and Galluccio, Michele and Tesulov, Mateja and Morelli, Emanuela and Sonmez, Fatma Mujgan and Bilguvar, Kaya and Ohgaki, Ryuichi and Kanai, Yoshikatsu and Johansen, Anide and Esharif, Seham and Ben-Omran, Tawfeg and Topcu, Meral and Schlessinger, Avner and Indiveri, Cesare and Duncan, Kent E and {\c C}a{\u g}layan, Ahmet Okay and G{\"u}nel, Murat and Gleeson, Joseph G and Novarino, Gaia} } @article {42, title = {Mutational Spectrum of MYO15A and the Molecular Mechanisms of DFNB3 Human Deafness.}, journal = {Hum Mutat}, volume = {37}, year = {2016}, month = {2016 10}, pages = {991-1003}, abstract = {

Deafness in humans is a common neurosensory disorder and is genetically heterogeneous. Across diverse ethnic groups, mutations of MYO15A at the DFNB3 locus appear to be the third or fourth most common cause of autosomal-recessive, nonsyndromic deafness. In 49 of the 67 exons of MYO15A, there are currently 192 recessive mutations identified, including 14 novel mutations reported here. These mutations are distributed uniformly across MYO15A with one enigmatic exception; the alternatively spliced giant exon 2, encoding 1,233 residues, has 17 truncating mutations but no convincing deafness-causing missense mutations. MYO15A encodes three distinct isoform classes, one of which is 395 kDa (3,530 residues), the largest member of the myosin superfamily of molecular motors. Studies of Myo15 mouse models that recapitulate DFNB3 revealed two different pathogenic mechanisms of hearing loss. In the inner ear, myosin 15 is necessary both for the development and the long-term maintenance of stereocilia, mechanosensory sound-transducing organelles that extend from the apical surface of hair cells. The goal of this Mutation Update is to provide a comprehensive review of mutations and functions of MYO15A.

}, keywords = {Alternative Splicing, Animals, Deafness, Disease Models, Animal, Ear, Inner, Exons, Gene Expression Regulation, Developmental, Humans, Mice, Mutation, Myosins, Stereocilia}, issn = {1098-1004}, doi = {10.1002/humu.23042}, author = {Rehman, Atteeq U and Bird, Jonathan E and Faridi, Rabia and Shahzad, Mohsin and Shah, Sujay and Lee, Kwanghyuk and Khan, Shaheen N and Imtiaz, Ayesha and Ahmed, Zubair M and Riazuddin, Saima and Santos-Cortez, Regie Lyn P and Ahmad, Wasim and Leal, Suzanne M and Riazuddin, Sheikh and Friedman, Thomas B} } @article {84, title = {Mutations in nuclear pore genes NUP93, NUP205 and XPO5 cause steroid-resistant nephrotic syndrome.}, journal = {Nat Genet}, volume = {48}, year = {2016}, month = {2016 Apr}, pages = {457-65}, abstract = {

Nucleoporins are essential components of the nuclear pore complex (NPC). Only a few diseases have been attributed to NPC dysfunction. Steroid-resistant nephrotic syndrome (SRNS), a frequent cause of chronic kidney disease, is caused by dysfunction of glomerular podocytes. Here we identify in eight families with SRNS mutations in NUP93, its interaction partner NUP205 or XPO5 (encoding exportin 5) as hitherto unrecognized monogenic causes of SRNS. NUP93 mutations caused disrupted NPC assembly. NUP93 knockdown reduced the presence of NUP205 in the NPC, and, reciprocally, a NUP205 alteration abrogated NUP93 interaction. We demonstrate that NUP93 and exportin 5 interact with the signaling protein SMAD4 and that NUP93 mutations abrogated interaction with SMAD4. Notably, NUP93 mutations interfered with BMP7-induced SMAD transcriptional reporter activity. We hereby demonstrate that mutations of NUP genes cause a distinct renal disease and identify aberrant SMAD signaling as a new disease mechanism of SRNS, opening a potential new avenue for treatment.

}, keywords = {Age of Onset, Amino Acid Sequence, Animals, Cell Movement, Cell Proliferation, Cells, Cultured, Child, Child, Preschool, Drug Resistance, Female, Genes, Recessive, Genetic Association Studies, Genetic Linkage, HEK293 Cells, Humans, Infant, Karyopherins, Male, Mice, Molecular Sequence Data, Mutation, Nephrotic Syndrome, Nuclear Pore Complex Proteins, Oxidative Stress, Podocytes, Sequence Analysis, DNA, Steroids, Xenopus laevis}, issn = {1546-1718}, doi = {10.1038/ng.3512}, author = {Braun, Daniela A and Sadowski, Carolin E and Kohl, Stefan and Lovric, Svjetlana and Astrinidis, Susanne A and Pabst, Werner L and Gee, Heon Yung and Ashraf, Shazia and Lawson, Jennifer A and Shril, Shirlee and Airik, Merlin and Tan, Weizhen and Schapiro, David and Rao, Jia and Choi, Won-Il and Hermle, Tobias and Kemper, Markus J and Pohl, Martin and Ozaltin, Fatih and Konrad, Martin and Bogdanovic, Radovan and B{\"u}scher, Rainer and Helmchen, Udo and Serdaroglu, Erkin and Lifton, Richard P and Antonin, Wolfram and Hildebrandt, Friedhelm} } @article {122, title = {Allelic Mutations of KITLG, Encoding KIT Ligand, Cause Asymmetric and Unilateral Hearing Loss and Waardenburg Syndrome Type 2.}, journal = {Am J Hum Genet}, volume = {97}, year = {2015}, month = {2015 Nov 05}, pages = {647-60}, abstract = {

Linkage analysis combined with whole-exome sequencing in a large family with congenital and stable non-syndromic unilateral and asymmetric hearing loss (NS-UHL/AHL) revealed a heterozygous truncating mutation, c.286_303delinsT (p.Ser96Ter), in KITLG. This mutation co-segregated with NS-UHL/AHL as a dominant trait with reduced penetrance. By screening a panel of probands with NS-UHL/AHL, we found an additional mutation, c.200_202del (p.His67_Cys68delinsArg). In~vitro studies revealed that the p.His67_Cys68delinsArg transmembrane isoform of KITLG is not detectable at the cell membrane, supporting pathogenicity. KITLG encodes a ligand for the KIT receptor. Also, KITLG-KIT signaling and MITF are suggested to mutually interact in melanocyte development. Because mutations in MITF are causative of Waardenburg syndrome type 2 (WS2), we screened KITLG in suspected WS2-affected probands. A heterozygous missense mutation, c.310C>G (p.Leu104Val), that segregated with WS2 was identified in a small family. In~vitro studies revealed that the p.Leu104Val transmembrane isoform of KITLG is located at the cell membrane, as is wild-type KITLG. However, in culture media of transfected cells, the p.Leu104Val soluble isoform of KITLG was reduced, and no soluble p.His67_Cys68delinsArg and p.Ser96Ter KITLG could be detected. These data suggest that mutations in KITLG associated with NS-UHL/AHL have a loss-of-function effect. We speculate that the mechanism of the mutation underlying WS2 and leading to membrane incorporation and reduced secretion of KITLG occurs via a dominant-negative or gain-of-function effect. Our study unveils different phenotypes associated with KITLG, previously associated with pigmentation abnormalities, and will thereby improve the genetic counseling given to individuals with KITLG variants.

}, keywords = {Alleles, Animals, Female, Fluorescent Antibody Technique, Genetic Linkage, Hearing Loss, Unilateral, Humans, Male, Mice, Mutation, NIH 3T3 Cells, Pedigree, Phenotype, Prognosis, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, RNA, Messenger, Stem Cell Factor, Waardenburg Syndrome}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.09.011}, author = {Zazo Seco, Celia and Serr{\~a}o de Castro, Luciana and van Nierop, Josephine W and Mor{\'\i}n, Mat{\'\i}as and Jhangiani, Shalini and Verver, Eva J J and Schraders, Margit and Maiwald, Nadine and Wesdorp, Mieke and Venselaar, Hanka and Spruijt, Liesbeth and Oostrik, Jaap and Schoots, Jeroen and van Reeuwijk, Jeroen and Lelieveld, Stefan H and Huygen, Patrick L M and Insenser, Mar{\'\i}a and Admiraal, Ronald J C and Pennings, Ronald J E and Hoefsloot, Lies H and Arias-V{\'a}squez, Alejandro and de Ligt, Joep and Yntema, Helger G and Jansen, Joop H and Muzny, Donna M and Huls, Gerwin and van Rossum, Michelle M and Lupski, James R and Moreno-Pelayo, Miguel Angel and Kunst, Henricus P M and Kremer, Hannie} } @article {212, title = {CNV instability associated with DNA replication dynamics: evidence for replicative mechanisms in CNV mutagenesis.}, journal = {Hum Mol Genet}, volume = {24}, year = {2015}, month = {2015 Mar 15}, pages = {1574-83}, abstract = {

Copy number variation (CNV) in the human genome is of vital importance to human health and evolution of our species. However, much of the molecular basis of CNV mutagenesis remains to be elucidated. Considering the DNA replication model of {\textquoteright}fork stalling and template switching{\textquoteright} for CNV formation, we hypothesized that replication fork progression could be important for CNV mutagenesis. However, molecular assays of replication fork progression at the genome level are technically challenging. Instead, we conducted an estimation of DNA replication dynamics, as the statistic R, using the readily available data of replication timing. Small R-values can reflect {\textquoteright}slowed{\textquoteright} replication, which could result from less fork initiation, reduced fork speed or fork barriers. We generated genome-wide profiles of R in the genomes of human, mouse and Drosophila. Intriguingly, the CNV breakpoints in all three genomes showed significantly biased distributions toward the genomic regions with small R-values, suggesting potential replication stress-induced CNV instability. Notably, among the human CNVs with distinct breakpoint junction characteristics, the homology-mediated and VNTR-mediated CNVs contribute the most to the correlation between CNV instability and the statistic R, consistent with the recent findings in the C. elegans and yeast genomes of repeat-induced DNA replication error and consequent CNV formation. The statistic R may reflect both replication stress and the effect of local genome architecture on fork progression. Our concordant observations suggest an important role for DNA replicative mechanisms in CNV mutagenesis and genome instability.

}, keywords = {Animals, DNA Copy Number Variations, DNA Replication, Drosophila, Genome, Genomic Instability, Humans, Mice}, issn = {1460-2083}, doi = {10.1093/hmg/ddu572}, author = {Chen, Lu and Zhou, Weichen and Zhang, Cheng and Lupski, James R and Jin, Li and Zhang, Feng} } @article {168, title = {Exome sequencing reveals pathogenic mutations in 91 strains of mice with Mendelian disorders.}, journal = {Genome Res}, volume = {25}, year = {2015}, month = {2015 Jul}, pages = {948-57}, abstract = {

Spontaneously arising mouse mutations have served as the foundation for understanding gene function for more than 100 years. We have used exome sequencing in an effort to identify the causative mutations for 172 distinct, spontaneously arising mouse models of Mendelian disorders, including a broad range of clinically relevant phenotypes. To analyze the resulting data, we developed an analytics pipeline that is optimized for mouse exome data and a variation database that allows for reproducible, user-defined data mining as well as nomination of mutation candidates through knowledge-based integration of sample and variant data. Using these new tools, putative pathogenic mutations were identified for 91 (53\%) of the strains in our study. Despite the increased power offered by potentially unlimited pedigrees and controlled breeding, about half of our exome cases remained unsolved. Using a combination of manual analyses of exome alignments and whole-genome sequencing, we provide evidence that a large fraction of unsolved exome cases have underlying structural mutations. This result directly informs efforts to investigate the similar proportion of apparently Mendelian human phenotypes that are recalcitrant to exome sequencing.

}, keywords = {Animals, Exome, Female, Genetic Diseases, Inborn, Genetic Linkage, Genetic Variation, Genome-Wide Association Study, Genomics, High-Throughput Nucleotide Sequencing, Male, Mice, Mutation, Phenotype, Reproducibility of Results}, issn = {1549-5469}, doi = {10.1101/gr.186882.114}, author = {Fairfield, Heather and Srivastava, Anuj and Ananda, Guruprasad and Liu, Rangjiao and Kircher, Martin and Lakshminarayana, Anuradha and Harris, Belinda S and Karst, Son Yong and Dionne, Louise A and Kane, Coleen C and Curtain, Michelle and Berry, Melissa L and Ward-Bailey, Patricia F and Greenstein, Ian and Byers, Candice and Czechanski, Anne and Sharp, Jocelyn and Palmer, Kristina and Gudis, Polyxeni and Martin, Whitney and Tadenev, Abby and Bogdanik, Laurent and Pratt, C Herbert and Chang, Bo and Schroeder, David G and Cox, Gregory A and Cliften, Paul and Milbrandt, Jeffrey and Murray, Stephen and Burgess, Robert and Bergstrom, David E and Donahue, Leah Rae and Hamamy, Hanan and Masri, Amira and Santoni, Federico A and Makrythanasis, Periklis and Antonarakis, Stylianos E and Shendure, Jay and Reinholdt, Laura G} } @article {157, title = {Mutation of ATF6 causes autosomal recessive achromatopsia.}, journal = {Hum Genet}, volume = {134}, year = {2015}, month = {2015 Sep}, pages = {941-50}, abstract = {

Achromatopsia (ACHM) is an early-onset retinal dystrophy characterized by photophobia, nystagmus, color blindness and severely reduced visual acuity. Currently mutations in five genes CNGA3, CNGB3, GNAT2, PDE6C and PDE6H have been implicated in ACHM. We performed homozygosity mapping and linkage analysis in a consanguineous Pakistani ACHM family and mapped the locus to a 15.12-Mb region on chromosome 1q23.1-q24.3 with a maximum LOD score of 3.6. A DNA sample from an affected family member underwent exome sequencing. Within the ATF6 gene, a single-base insertion variant c.355_356dupG (p.Glu119Glyfs*8) was identified, which completely segregates with the ACHM phenotype within the family. The frameshift variant was absent in public variant databases, in 130 exomes from unrelated Pakistani individuals, and in 235 ethnically matched controls. The variant is predicted to result in a truncated protein that lacks the DNA binding and transmembrane domains and therefore affects the function of ATF6 as a transcription factor that initiates the unfolded protein response during endoplasmic reticulum (ER) stress. Immunolabeling with anti-ATF6 antibodies showed localization throughout the mouse neuronal retina, including retinal pigment epithelium, photoreceptor cells, inner nuclear layer, inner and outer plexiform layers, with a more prominent signal in retinal ganglion cells. In contrast to cytoplasmic expression of wild-type protein, in heterologous cells ATF6 protein with the p.Glu119Glyfs*8 variant is mainly confined to the nucleus. Our results imply that response to ER stress as mediated by the ATF6 pathway is essential for color vision in humans.

}, keywords = {Activating Transcription Factor 6, Adolescent, Animals, Asian Continental Ancestry Group, Color Vision Defects, Consanguinity, DNA Mutational Analysis, Exome, Female, Frameshift Mutation, Genotyping Techniques, Homozygote, Humans, Limit of Detection, Male, Mice, Mice, Inbred C57BL, Pakistan, Pedigree, Phenotype, Retina, Signal Transduction}, issn = {1432-1203}, doi = {10.1007/s00439-015-1571-4}, author = {Ansar, Muhammad and Santos-Cortez, Regie Lyn P and Saqib, Muhammad Arif Nadeem and Zulfiqar, Fareeha and Lee, Kwanghyuk and Ashraf, Naeem Mahmood and Ullah, Ehsan and Wang, Xin and Sajid, Sundus and Khan, Falak Sher and Amin-ud-Din, Muhammad and Smith, Joshua D and Shendure, Jay and Bamshad, Michael J and Nickerson, Deborah A and Hameed, Abdul and Riazuddin, Saima and Ahmed, Zubair M and Ahmad, Wasim and Leal, Suzanne M} } @article {267, title = {Adenylate cyclase 1 (ADCY1) mutations cause recessive hearing impairment in humans and defects in hair cell function and hearing in zebrafish.}, journal = {Hum Mol Genet}, volume = {23}, year = {2014}, month = {2014 Jun 15}, pages = {3289-98}, abstract = {

Cyclic AMP (cAMP) production, which is important for mechanotransduction within the inner ear, is catalyzed by adenylate cyclases (AC). However, knowledge of the role of ACs in hearing is limited. Previously, a novel autosomal recessive non-syndromic hearing impairment locus DFNB44 was mapped to chromosome 7p14.1-q11.22 in a consanguineous family from Pakistan. Through whole-exome sequencing of DNA samples from hearing-impaired family members, a nonsense mutation c.3112C>T (p.Arg1038*) within adenylate cyclase 1 (ADCY1) was identified. This stop-gained mutation segregated with hearing impairment within the family and was not identified in ethnically matched controls or within variant databases. This mutation is predicted to cause the loss of 82 amino acids from the carboxyl tail, including highly conserved residues within the catalytic domain, plus a calmodulin-stimulation defect, both of which are expected to decrease enzymatic efficiency. Individuals who are homozygous for this mutation had symmetric, mild-to-moderate mixed hearing impairment. Zebrafish adcy1b morphants had no FM1-43 dye uptake and lacked startle response, indicating hair cell dysfunction and gross hearing impairment. In the mouse, Adcy1 expression was observed throughout inner ear development and maturation. ADCY1 was localized to the cytoplasm of supporting cells and hair cells of the cochlea and vestibule and also to cochlear hair cell nuclei and stereocilia. Ex vivo studies in COS-7 cells suggest that the carboxyl tail of ADCY1 is essential for localization to actin-based microvilli. These results demonstrate that ADCY1 has an evolutionarily conserved role in hearing and that cAMP signaling is important to hair cell function within the inner ear.

}, keywords = {Adenylyl Cyclases, Animals, Cercopithecus aethiops, Codon, Nonsense, COS Cells, Cyclic AMP, Cytoplasm, Ear, Inner, Female, Hair Cells, Auditory, Hearing Loss, Humans, Labyrinth Supporting Cells, Male, Mice, Zebrafish}, issn = {1460-2083}, doi = {10.1093/hmg/ddu042}, author = {Santos-Cortez, Regie Lyn P and Lee, Kwanghyuk and Giese, Arnaud P and Ansar, Muhammad and Amin-ud-Din, Muhammad and Rehn, Kira and Wang, Xin and Aziz, Abdul and Chiu, Ilene and Hussain Ali, Raja and Smith, Joshua D and Shendure, Jay and Bamshad, Michael and Nickerson, Deborah A and Ahmed, Zubair M and Ahmad, Wasim and Riazuddin, Saima and Leal, Suzanne M} } @article {252, title = {CLP1 founder mutation links tRNA splicing and maturation to cerebellar development and neurodegeneration.}, journal = {Cell}, volume = {157}, year = {2014}, month = {2014 Apr 24}, pages = {651-63}, abstract = {

Neurodegenerative diseases can occur so early as to affect neurodevelopment. From a cohort of more than 2,000 consanguineous families with childhood neurological disease, we identified a founder mutation in four independent pedigrees in cleavage and polyadenylation factor I subunit 1 (CLP1). CLP1 is a multifunctional kinase implicated in tRNA, mRNA, and siRNA maturation. Kinase activity of the CLP1 mutant protein was defective, and the tRNA endonuclease complex (TSEN) was destabilized, resulting in impaired pre-tRNA cleavage. Germline clp1 null zebrafish showed cerebellar neurodegeneration that was rescued by wild-type, but not mutant, human CLP1 expression. Patient-derived induced neurons displayed both depletion of mature tRNAs and accumulation of unspliced pre-tRNAs. Transfection of partially processed tRNA fragments into patient cells exacerbated an oxidative stress-induced reduction in cell survival. Our data link tRNA maturation to neuronal development and neurodegeneration through defective CLP1 function in humans.

}, keywords = {Animals, Brain, Cerebellum, Cleavage And Polyadenylation Specificity Factor, Female, Humans, Male, Mice, Models, Molecular, Neurodegenerative Diseases, Nuclear Proteins, Pedigree, Phosphotransferases, RNA Splicing, RNA, Transfer, Saccharomyces cerevisiae, Transcription Factors, Zebrafish, Zebrafish Proteins}, issn = {1097-4172}, doi = {10.1016/j.cell.2014.03.049}, author = {Schaffer, Ashleigh E and Eggens, Veerle R C and {\c C}a{\u g}layan, Ahmet Okay and Reuter, Miriam S and Scott, Eric and Coufal, Nicole G and Silhavy, Jennifer L and Xue, Yuanchao and Kayserili, H{\"u}lya and Yasuno, Katsuhito and Rosti, Rasim Ozgur and Abdellateef, Mostafa and Caglar, Caner and Kasher, Paul R and Cazemier, J Leonie and Weterman, Marian A and Cantagrel, Vincent and Cai, Na and Zweier, Christiane and Altunoglu, Umut and Satkin, N Bilge and Aktar, Fesih and Tuysuz, Beyhan and Yalcinkaya, Cengiz and Caksen, Huseyin and Bilguvar, Kaya and Fu, Xiang-Dong and Trotta, Christopher R and Gabriel, Stacey and Reis, Andr{\'e} and G{\"u}nel, Murat and Baas, Frank and Gleeson, Joseph G} } @article {227, title = {Exome sequencing identifies a recurrent de novo ZSWIM6 mutation associated with acromelic frontonasal dysostosis.}, journal = {Am J Hum Genet}, volume = {95}, year = {2014}, month = {2014 Aug 07}, pages = {235-40}, abstract = {

Acromelic frontonasal dysostosis (AFND) is a rare disorder characterized by distinct craniofacial, brain, and limb malformations, including frontonasal dysplasia, interhemispheric lipoma, agenesis of the corpus callosum, tibial hemimelia, preaxial polydactyly of the feet, and intellectual disability. Exome sequencing of one trio and two unrelated probands revealed the same heterozygous variant (c.3487C>T [p. Arg1163Trp]) in a highly conserved protein domain of ZSWIM6; this variant has not been seen in the 1000 Genomes data, dbSNP, or the Exome Sequencing Project. Sanger validation of the three trios confirmed that the variant was de novo and was also present in a fourth isolated proband. In situ hybridization of early zebrafish embryos at 24 hr postfertilization (hpf) demonstrated telencephalic expression of zswim6 and onset of midbrain, hindbrain, and retinal expression at 48 hpf. Immunohistochemistry of later-stage mouse embryos demonstrated tissue-specific expression in the derivatives of all three germ layers. qRT-PCR expression analysis of osteoblast and fibroblast cell lines available from two probands was suggestive of Hedgehog pathway activation, indicating that the ZSWIM6 mutation associated with AFND may lead to the craniofacial, brain and limb malformations through the disruption of Hedgehog signaling.

}, keywords = {Abnormalities, Multiple, Amino Acid Sequence, Animals, Base Sequence, Craniofacial Abnormalities, DNA Mutational Analysis, DNA-Binding Proteins, Exome, Face, Hedgehog Proteins, Humans, Intellectual Disability, Limb Deformities, Congenital, Mandibulofacial Dysostosis, Mice, Molecular Sequence Data, Mutation, Protein Structure, Tertiary, Zebrafish, Zinc Fingers}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.07.008}, author = {Smith, Joshua D and Hing, Anne V and Clarke, Christine M and Johnson, Nathan M and Perez, Francisco A and Park, Sarah S and Horst, Jeremy A and Mecham, Brig and Maves, Lisa and Nickerson, Deborah A and Cunningham, Michael L} } @article {253, title = {Human CLP1 mutations alter tRNA biogenesis, affecting both peripheral and central nervous system function.}, journal = {Cell}, volume = {157}, year = {2014}, month = {2014 Apr 24}, pages = {636-50}, abstract = {

CLP1 is a RNA kinase involved in tRNA splicing. Recently, CLP1 kinase-dead mice were shown to display a neuromuscular disorder with loss of motor neurons and muscle paralysis. Human genome analyses now identified a CLP1 homozygous missense mutation (p.R140H) in five unrelated families, leading to a loss of CLP1 interaction with the tRNA splicing endonuclease (TSEN) complex, largely reduced pre-tRNA cleavage activity, and accumulation of linear tRNA introns. The affected individuals develop severe motor-sensory defects, cortical dysgenesis, and microcephaly. Mice carrying kinase-dead CLP1 also displayed microcephaly and reduced cortical brain volume due to the enhanced cell death of neuronal progenitors that is associated with reduced numbers of cortical neurons. Our data elucidate a neurological syndrome defined by CLP1 mutations that impair tRNA splicing. Reduction of a founder mutation to homozygosity illustrates the importance of rare variations in disease and supports the clan genomics hypothesis.

}, keywords = {Abnormalities, Multiple, Animals, Central Nervous System Diseases, Cerebrum, Child, Preschool, Endoribonucleases, Female, Fibroblasts, Humans, Infant, Male, Mice, Mice, Inbred CBA, Microcephaly, Mutation, Missense, Nuclear Proteins, Peripheral Nervous System Diseases, Phosphotransferases, RNA, Transfer, Transcription Factors}, issn = {1097-4172}, doi = {10.1016/j.cell.2014.02.058}, author = {Karaca, Ender and Weitzer, Stefan and Pehlivan, Davut and Shiraishi, Hiroshi and Gogakos, Tasos and Hanada, Toshikatsu and Jhangiani, Shalini N and Wiszniewski, Wojciech and Withers, Marjorie and Campbell, Ian M and Erdin, Serkan and Isikay, Sedat and Franco, Luis M and Gonzaga-Jauregui, Claudia and Gambin, Tomasz and Gelowani, Violet and Hunter, Jill V and Yesil, G{\"o}zde and Koparir, Erkan and Yilmaz, Sarenur and Brown, Miguel and Briskin, Daniel and Hafner, Markus and Morozov, Pavel and Farazi, Thalia A and Bernreuther, Christian and Glatzel, Markus and Trattnig, Siegfried and Friske, Joachim and Kronnerwetter, Claudia and Bainbridge, Matthew N and Gezdirici, Alper and Seven, Mehmet and Muzny, Donna M and Boerwinkle, Eric and Ozen, Mustafa and Clausen, Tim and Tuschl, Thomas and Yuksel, Adnan and Hess, Andreas and Gibbs, Richard A and Martinez, Javier and Penninger, Josef M and Lupski, James R} } @article {243, title = {Monoallelic and biallelic mutations in MAB21L2 cause a spectrum of major eye malformations.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 Jun 05}, pages = {915-23}, abstract = {

We identified four different missense mutations in the single-exon gene MAB21L2 in eight individuals with bilateral eye malformations from five unrelated families via three independent exome sequencing projects. Three mutational events altered the same amino acid (Arg51), and two were identical de novo mutations (c.151C>T [p.Arg51Cys]) in unrelated children with bilateral anophthalmia, intellectual disability, and rhizomelic skeletal dysplasia. c.152G>A (p.Arg51His) segregated with autosomal-dominant bilateral colobomatous microphthalmia in a large multiplex family. The fourth heterozygous mutation (c.145G>A [p.Glu49Lys]) affected an amino acid within two residues of Arg51 in an adult male with bilateral colobomata. In a fifth family, a homozygous mutation (c.740G>A [p.Arg247Gln]) altering a different region of the protein was identified in two male siblings with bilateral retinal colobomata. In mouse embryos, Mab21l2 showed strong expression in the developing eye, pharyngeal arches, and limb bud. As predicted by structural homology, wild-type MAB21L2 bound single-stranded RNA, whereas this activity was lost in all altered forms of the protein. MAB21L2 had no detectable nucleotidyltransferase activity in~vitro, and its function remains unknown. Induced expression of wild-type MAB21L2 in human embryonic kidney 293 cells increased phospho-ERK (pERK1/2) signaling. Compared to the wild-type and p.Arg247Gln proteins, the proteins with the Glu49 and Arg51 variants had increased stability. Abnormal persistence of pERK1/2 signaling in MAB21L2-expressing cells during development is a plausible pathogenic mechanism for the heterozygous mutations. The phenotype associated with the homozygous mutation might be a consequence of complete loss of MAB21L2 RNA binding, although the cellular function of this interaction remains unknown.

}, keywords = {Adult, Alleles, Animals, Anophthalmos, Brain Diseases, Metabolic, Inborn, Coloboma, Corneal Opacity, Exome, Eye Proteins, Female, Gene Expression, HEK293 Cells, Heterozygote, Homozygote, Humans, Intellectual Disability, Intracellular Signaling Peptides and Proteins, Male, Mice, Microcephaly, Microphthalmos, Mutation, Missense, Pedigree, Phenotype, Protein Conformation, Signal Transduction}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.05.005}, author = {Rainger, Joe and Pehlivan, Davut and Johansson, Stefan and Bengani, Hemant and Sanchez-Pulido, Luis and Williamson, Kathleen A and Ture, Mehmet and Barker, Heather and Rosendahl, Karen and Spranger, J{\"u}rgen and Horn, Denise and Meynert, Alison and Floyd, James A B and Prescott, Trine and Anderson, Carl A and Rainger, Jacqueline K and Karaca, Ender and Gonzaga-Jauregui, Claudia and Jhangiani, Shalini and Muzny, Donna M and Seawright, Anne and Soares, Dinesh C and Kharbanda, Mira and Murday, Victoria and Finch, Andrew and Gibbs, Richard A and van Heyningen, Veronica and Taylor, Martin S and Yakut, Tahsin and Knappskog, Per M and Hurles, Matthew E and Ponting, Chris P and Lupski, James R and Houge, Gunnar and FitzPatrick, David R} } @article {261, title = {Mutations in Alstr{\"o}m protein impair terminal differentiation of cardiomyocytes.}, journal = {Nat Commun}, volume = {5}, year = {2014}, month = {2014 Mar 04}, pages = {3416}, abstract = {

Cardiomyocyte cell division and replication in mammals proceed through embryonic development and abruptly decline soon after birth. The process governing cardiomyocyte cell cycle arrest is poorly understood. Here we carry out whole-exome sequencing in an infant with evidence of persistent postnatal cardiomyocyte replication to determine the genetic risk factors. We identify compound heterozygous ALMS1 mutations in the proband, and confirm their presence in her affected sibling, one copy inherited from each heterozygous parent. Next, we recognize homozygous or compound heterozygous truncating mutations in ALMS1 in four other children with high levels of postnatal cardiomyocyte proliferation. Alms1 mRNA knockdown increases multiple markers of proliferation in cardiomyocytes, the percentage of cardiomyocytes in G2/M phases, and the number of cardiomyocytes by 10\% in cultured cells. Homozygous Alms1-mutant mice have increased cardiomyocyte proliferation at 2 weeks postnatal compared with wild-type littermates. We conclude that deficiency of Alstr{\"o}m protein impairs postnatal cardiomyocyte cell cycle arrest.

}, keywords = {Animals, Cell Cycle, Cell Differentiation, Cells, Cultured, DNA-Binding Proteins, Humans, Immunohistochemistry, Mice, Molecular Sequence Data, Mutation, Myocytes, Cardiac, Proteins, Reverse Transcriptase Polymerase Chain Reaction}, issn = {2041-1723}, doi = {10.1038/ncomms4416}, author = {Shenje, Lincoln T and Andersen, Peter and Halushka, Marc K and Lui, Cecillia and Fernandez, Laviel and Collin, Gayle B and Amat-Alarcon, Nuria and Meschino, Wendy and Cutz, Ernest and Chang, Kenneth and Yonescu, Raluca and Batista, Denise A S and Chen, Yan and Chelko, Stephen and Crosson, Jane E and Scheel, Janet and Vricella, Luca and Craig, Brian D and Marosy, Beth A and Mohr, David W and Hetrick, Kurt N and Romm, Jane M and Scott, Alan F and Valle, David and Naggert, J{\"u}rgen K and Kwon, Chulan and Doheny, Kimberly F and Judge, Daniel P} } @article {203, title = {Mutations in KATNB1 cause complex cerebral malformations by disrupting asymmetrically dividing neural progenitors.}, journal = {Neuron}, volume = {84}, year = {2014}, month = {2014 Dec 17}, pages = {1226-39}, abstract = {

Exome sequencing analysis of over 2,000 children with complex malformations of cortical development identified five independent (four homozygous and one compound heterozygous) deleterious mutations in KATNB1, encoding the regulatory subunit of the microtubule-severing enzyme Katanin. Mitotic spindle formation is defective in patient-derived fibroblasts, a consequence of disrupted interactions of mutant KATNB1 with KATNA1, the catalytic subunit of Katanin, and other microtubule-associated proteins. Loss of KATNB1 orthologs in zebrafish (katnb1) and flies (kat80) results in microcephaly, recapitulating the human phenotype. In the developing Drosophila optic lobe, kat80 loss specifically affects the asymmetrically dividing neuroblasts, which display supernumerary centrosomes and spindle abnormalities during mitosis, leading to cell cycle progression delays and reduced cell numbers. Furthermore, kat80 depletion results in dendritic arborization defects in sensory and motor neurons, affecting neural architecture. Taken together, we provide insight into the mechanisms by which KATNB1 mutations cause human cerebral cortical malformations, demonstrating its fundamental role during brain development.

}, keywords = {Adenosine Triphosphatases, Animals, Brain, Cell Count, Cell Division, Dendrites, Drosophila, Drosophila Proteins, Humans, Katanin, Mice, Microcephaly, Microtubule-Associated Proteins, Mutation, Neural Stem Cells, Neurogenesis, Optic Lobe, Nonmammalian, Spindle Apparatus, Zebrafish}, issn = {1097-4199}, doi = {10.1016/j.neuron.2014.12.014}, author = {Mishra-Gorur, Ketu and {\c C}a{\u g}layan, Ahmet Okay and Schaffer, Ashleigh E and Chabu, Chiswili and Henegariu, Octavian and Vonhoff, Fernando and Akg{\"u}m{\"u}{\c s}, G{\"o}zde Tu{\u g}ce and Nishimura, Sayoko and Han, Wenqi and Tu, Shu and Baran, Bur{\c c}in and G{\"u}m{\"u}{\c s}, Hakan and Dilber, Cengiz and Zaki, Maha S and Hossni, Heba A A and Rivi{\`e}re, Jean-Baptiste and Kayserili, H{\"u}lya and Spencer, Emily G and Rosti, Rasim O and Schroth, Jana and Per, H{\"u}seyin and Caglar, Caner and {\c C}a{\u g}lar, {\c C}a{\u g}ri and D{\"o}len, Duygu and Baranoski, Jacob F and Kumanda{\c s}, Sefer and Minja, Frank J and Erson-Omay, E Zeynep and Mane, Shrikant M and Lifton, Richard P and Xu, Tian and Keshishian, Haig and Dobyns, William B and Chi, Neil C and {\v S}estan, Nenad and Louvi, Angeliki and Bilguvar, Kaya and Yasuno, Katsuhito and Gleeson, Joseph G and G{\"u}nel, Murat} } @article {260, title = {Mutations in TJP2 cause progressive cholestatic liver disease.}, journal = {Nat Genet}, volume = {46}, year = {2014}, month = {2014 Apr}, pages = {326-8}, abstract = {

Elucidating genetic causes of cholestasis has proved to be important in understanding the physiology and pathophysiology of the liver. Here we show that protein-truncating mutations in the tight junction protein 2 gene (TJP2) cause failure of protein localization and disruption of tight-junction structure, leading to severe cholestatic liver disease. These findings contrast with those in the embryonic-lethal knockout mouse, highlighting differences in redundancy in junctional complexes between organs and species.

}, keywords = {Animals, Base Sequence, Cholestasis, Intrahepatic, High-Throughput Nucleotide Sequencing, Humans, Immunoblotting, Immunohistochemistry, Mice, Mice, Knockout, Microscopy, Electron, Transmission, Models, Biological, Molecular Sequence Data, Mutation, Pedigree, Real-Time Polymerase Chain Reaction, Sequence Alignment, Species Specificity, Tight Junctions, Zonula Occludens-2 Protein}, issn = {1546-1718}, doi = {10.1038/ng.2918}, author = {Sambrotta, Melissa and Strautnieks, Sandra and Papouli, Efterpi and Rushton, Peter and Clark, Barnaby E and Parry, David A and Logan, Clare V and Newbury, Lucy J and Kamath, Binita M and Ling, Simon and Grammatikopoulos, Tassos and Wagner, Bart E and Magee, John C and Sokol, Ronald J and Mieli-Vergani, Giorgina and Smith, Joshua D and Johnson, Colin A and McClean, Patricia and Simpson, Michael A and Knisely, A S and Bull, Laura N and Thompson, Richard J} } @article {296, title = {ARMC4 mutations cause primary ciliary dyskinesia with randomization of left/right body asymmetry.}, journal = {Am J Hum Genet}, volume = {93}, year = {2013}, month = {2013 Aug 08}, pages = {357-67}, abstract = {

The motive forces for ciliary movement are generated by large multiprotein complexes referred to as outer dynein arms (ODAs), which are preassembled in the cytoplasm prior to transport to the ciliary axonemal compartment. In humans, defects in structural components, docking complexes, or cytoplasmic assembly factors can cause primary ciliary dyskinesia (PCD), a disorder characterized by chronic airway disease and defects in laterality. By using combined high resolution copy-number variant and mutation analysis, we identified ARMC4 mutations in twelve PCD individuals whose cells showed reduced numbers of ODAs and severely impaired ciliary beating. Transient suppression in zebrafish and analysis of an ENU mouse mutant confirmed in both model organisms that ARMC4 is critical for left-right patterning. We demonstrate that ARMC4 is an axonemal protein that is necessary for proper targeting and anchoring of ODAs.

}, keywords = {Amino Acid Sequence, Animals, Armadillo Domain Proteins, Axoneme, Body Patterning, Cilia, DNA Copy Number Variations, DNA Mutational Analysis, Dyneins, Gene Expression Regulation, Humans, Kartagener Syndrome, Mice, Microtubule-Associated Proteins, Molecular Sequence Data, Mutation, Respiratory System, Zebrafish}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.06.009}, author = {Hjeij, Rim and Lindstrand, Anna and Francis, Richard and Zariwala, Maimoona A and Liu, Xiaoqin and Li, You and Damerla, Rama and Dougherty, Gerard W and Abouhamed, Marouan and Olbrich, Heike and Loges, Niki T and Pennekamp, Petra and Davis, Erica E and Carvalho, Claudia M B and Pehlivan, Davut and Werner, Claudius and Raidt, Johanna and K{\"o}hler, Gabriele and H{\"a}ffner, Karsten and Reyes-Mugica, Miguel and Lupski, James R and Leigh, Margaret W and Rosenfeld, Margaret and Morgan, Lucy C and Knowles, Michael R and Lo, Cecilia W and Katsanis, Nicholas and Omran, Heymut} } @article {295, title = {Mutations in DSTYK and dominant urinary tract malformations.}, journal = {N Engl J Med}, volume = {369}, year = {2013}, month = {2013 Aug 15}, pages = {621-9}, abstract = {

BACKGROUND: Congenital abnormalities of the kidney and the urinary tract are the most common cause of pediatric kidney failure. These disorders are highly heterogeneous, and the etiologic factors are poorly understood.

METHODS: We performed genomewide linkage analysis and whole-exome sequencing in a family with an autosomal dominant form of congenital abnormalities of the kidney or urinary tract (seven affected family members). We also performed a sequence analysis in 311 unrelated patients, as well as histologic and functional studies.

RESULTS: Linkage analysis identified five regions of the genome that were shared among all affected family members. Exome sequencing identified a single, rare, deleterious variant within these linkage intervals, a heterozygous splice-site mutation in the dual serine-threonine and tyrosine protein kinase gene (DSTYK). This variant, which resulted in aberrant splicing of messenger RNA, was present in all affected family members. Additional, independent DSTYK mutations, including nonsense and splice-site mutations, were detected in 7 of 311 unrelated patients. DSTYK is highly expressed in the maturing epithelia of all major organs, localizing to cell membranes. Knockdown in zebrafish resulted in developmental defects in multiple organs, which suggested loss of fibroblast growth factor (FGF) signaling. Consistent with this finding is the observation that DSTYK colocalizes with FGF receptors in the ureteric bud and metanephric mesenchyme. DSTYK knockdown in human embryonic kidney cells inhibited FGF-stimulated phosphorylation of extracellular-signal-regulated kinase (ERK), the principal signal downstream of receptor tyrosine kinases.

CONCLUSIONS: We detected independent DSTYK mutations in 2.3\% of patients with congenital abnormalities of the kidney or urinary tract, a finding that suggests that DSTYK is a major determinant of human urinary tract development, downstream of FGF signaling. (Funded by the National Institutes of Health and others.).

}, keywords = {Adult, Animals, Base Sequence, Child, Exome, Female, Gene Knockdown Techniques, Genetic Linkage, Genome-Wide Association Study, Heterozygote, Humans, Infant, Kidney, Male, Mice, Molecular Sequence Data, Mutation, Pedigree, Receptor-Interacting Protein Serine-Threonine Kinases, RNA, Small Interfering, Urinary Tract, Urogenital Abnormalities, Young Adult}, issn = {1533-4406}, doi = {10.1056/NEJMoa1214479}, author = {Sanna-Cherchi, Simone and Sampogna, Rosemary V and Papeta, Natalia and Burgess, Katelyn E and Nees, Shannon N and Perry, Brittany J and Choi, Murim and Bodria, Monica and Liu, Yan and Weng, Patricia L and Lozanovski, Vladimir J and Verbitsky, Miguel and Lugani, Francesca and Sterken, Roel and Paragas, Neal and Caridi, Gianluca and Carrea, Alba and Dagnino, Monica and Materna-Kiryluk, Anna and Santamaria, Giuseppe and Murtas, Corrado and Ristoska-Bojkovska, Nadica and Izzi, Claudia and Kacak, Nilgun and Bianco, Beatrice and Giberti, Stefania and Gigante, Maddalena and Piaggio, Giorgio and Gesualdo, Loreto and Vukic, Durdica Kosuljandic and Vukojevic, Katarina and Saraga-Babic, Mirna and Saraga, Marijan and Gucev, Zoran and Allegri, Landino and Latos-Bielenska, Anna and Casu, Domenica and State, Matthew and Scolari, Francesco and Ravazzolo, Roberto and Kiryluk, Krzysztof and Al-Awqati, Qais and D{\textquoteright}Agati, Vivette D and Drummond, Iain A and Tasic, Velibor and Lifton, Richard P and Ghiggeri, Gian Marco and Gharavi, Ali G} } @article {299, title = {Mutations in KARS, encoding lysyl-tRNA synthetase, cause autosomal-recessive nonsyndromic hearing impairment DFNB89.}, journal = {Am J Hum Genet}, volume = {93}, year = {2013}, month = {2013 Jul 11}, pages = {132-40}, abstract = {

Previously, DFNB89, a locus associated with autosomal-recessive nonsyndromic hearing impairment (ARNSHI), was mapped to chromosomal region 16q21-q23.2 in three unrelated, consanguineous Pakistani families. Through whole-exome sequencing of a hearing-impaired individual from each family, missense mutations were identified at highly conserved residues of lysyl-tRNA synthetase (KARS): the c.1129G>A (p.Asp377Asn) variant was found in one family, and the c.517T>C (p.Tyr173His) variant was found in the other two families. Both variants were predicted to be damaging by multiple bioinformatics tools. The two variants both segregated with the nonsyndromic-hearing-impairment phenotype within the three families, and neither mutation was identified in ethnically matched controls or within variant databases. Individuals homozygous for KARS mutations had symmetric, severe hearing impairment across all frequencies but did not show evidence of auditory or limb neuropathy. It has been demonstrated that KARS is expressed in hair cells of zebrafish, chickens, and mice. Moreover, KARS has strong localization to the spiral ligament region of the cochlea, as well as to Deiters{\textquoteright} cells, the sulcus epithelium, the basilar membrane, and the surface of the spiral limbus. It is hypothesized that KARS variants affect aminoacylation in inner-ear cells by interfering with binding activity to tRNA or p38 and with tetramer formation. The identification of rare KARS variants in ARNSHI-affected families defines a gene that is associated with ARNSHI.

}, keywords = {Animals, Case-Control Studies, Chickens, Cochlea, Computational Biology, Consanguinity, Female, Genetic Linkage, Hair Cells, Auditory, Inner, Haplotypes, Hearing Loss, Homozygote, Humans, Lysine-tRNA Ligase, Male, Mice, Mutation, Missense, Pedigree, Transfer RNA Aminoacylation, Zebrafish}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2013.05.018}, author = {Santos-Cortez, Regie Lyn P and Lee, Kwanghyuk and Azeem, Zahid and Antonellis, Patrick J and Pollock, Lana M and Khan, Saadullah and Andrade-Elizondo, Paula B and Chiu, Ilene and Adams, Mark D and Basit, Sulman and Smith, Joshua D and Nickerson, Deborah A and McDermott, Brian M and Ahmad, Wasim and Leal, Suzanne M} } @article {324, title = {Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm.}, journal = {Nat Genet}, volume = {44}, year = {2012}, month = {2012 Jul 08}, pages = {922-7}, abstract = {

Loeys-Dietz syndrome (LDS) associates with a tissue signature for high transforming growth factor (TGF)-β signaling but is often caused by heterozygous mutations in genes encoding positive effectors of TGF-β signaling, including either subunit of the TGF-β receptor or SMAD3, thereby engendering controversy regarding the mechanism of disease. Here, we report heterozygous mutations or deletions in the gene encoding the TGF-β2 ligand for a phenotype within the LDS spectrum and show upregulation of TGF-β signaling in aortic tissue from affected individuals. Furthermore, haploinsufficient Tgfb2(+/-) mice have aortic root aneurysm and biochemical evidence of increased canonical and noncanonical TGF-β signaling. Mice that harbor both a mutant Marfan syndrome (MFS) allele (Fbn1(C1039G/+)) and Tgfb2 haploinsufficiency show increased TGF-β signaling and phenotypic worsening in association with normalization of TGF-β2 expression and high expression of TGF-β1. Taken together, these data support the hypothesis that compensatory autocrine and/or paracrine events contribute to the pathogenesis of TGF-β-mediated vasculopathies.

}, keywords = {Animals, Aortic Aneurysm, Thoracic, Disease Models, Animal, Female, Fibrillin-1, Fibrillins, Haploinsufficiency, Humans, Loeys-Dietz Syndrome, Male, Marfan Syndrome, Mice, Mice, Knockout, Mice, Mutant Strains, Microfilament Proteins, Mutation, Pedigree, Phenotype, Signal Transduction, Syndrome, Transforming Growth Factor beta2}, issn = {1546-1718}, doi = {10.1038/ng.2349}, author = {Lindsay, Mark E and Schepers, Dorien and Bolar, Nikhita Ajit and Doyle, Jefferson J and Gallo, Elena and Fert-Bober, Justyna and Kempers, Marlies J E and Fishman, Elliot K and Chen, Yichun and Myers, Loretha and Bjeda, Djahita and Oswald, Gretchen and Elias, Abdallah F and Levy, Howard P and Anderlid, Britt-Marie and Yang, Margaret H and Bongers, Ernie M H F and Timmermans, Janneke and Braverman, Alan C and Canham, Natalie and Mortier, Geert R and Brunner, Han G and Byers, Peter H and Van Eyk, Jennifer and Van Laer, Lut and Dietz, Harry C and Loeys, Bart L} } @article {319, title = {Mutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm.}, journal = {Nat Genet}, volume = {44}, year = {2012}, month = {2012 Nov}, pages = {1249-54}, abstract = {

Elevated transforming growth factor (TGF)-β signaling has been implicated in the pathogenesis of syndromic presentations of aortic aneurysm, including Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS). However, the location and character of many of the causal mutations in LDS intuitively imply diminished TGF-β signaling. Taken together, these data have engendered controversy regarding the specific role of TGF-β in disease pathogenesis. Shprintzen-Goldberg syndrome (SGS) has considerable phenotypic overlap with MFS and LDS, including aortic aneurysm. We identified causative variation in ten individuals with SGS in the proto-oncogene SKI, a known repressor of TGF-β activity. Cultured dermal fibroblasts from affected individuals showed enhanced activation of TGF-β signaling cascades and higher expression of TGF-β-responsive genes relative to control cells. Morpholino-induced silencing of SKI paralogs in zebrafish recapitulated abnormalities seen in humans with SGS. These data support the conclusions that increased TGF-β signaling is the mechanism underlying SGS and that high signaling contributes to multiple syndromic presentations of aortic aneurysm.

}, keywords = {Animals, Aortic Aneurysm, Arachnodactyly, Cells, Cultured, Craniosynostoses, DNA-Binding Proteins, Fibroblasts, Humans, Loeys-Dietz Syndrome, Marfan Syndrome, Mice, Mutation, Phenotype, Phosphorylation, Proto-Oncogene Proteins, Signal Transduction, Transforming Growth Factor beta, Zebrafish}, issn = {1546-1718}, doi = {10.1038/ng.2421}, author = {Doyle, Alexander J and Doyle, Jefferson J and Bessling, Seneca L and Maragh, Samantha and Lindsay, Mark E and Schepers, Dorien and Gillis, Elisabeth and Mortier, Geert and Homfray, Tessa and Sauls, Kimberly and Norris, Russell A and Huso, Nicholas D and Leahy, Dan and Mohr, David W and Caulfield, Mark J and Scott, Alan F and Destr{\'e}e, Anne and Hennekam, Raoul C and Arn, Pamela H and Curry, Cynthia J and Van Laer, Lut and McCallion, Andrew S and Loeys, Bart L and Dietz, Harry C} }